Benzimidazole tetrahydropyran derivatives

ABSTRACT

Novel compounds described herein are activators of AMP-protein kinase and may be useful in the treatment, prevention and suppression of diseases mediated by the AMPKactivated protein kinase. The compounds of the present invention may be useful in the treatment of Type 2 diabetes, hyperglycemia, metabolic syndrome, obesity, hypercholesterolemia, and hypertension.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C.§371 of PCT Application No. PCT/US2013/055177, filed on Aug. 15, 2013,which claims priority from and the benefit of U.S. ProvisionalApplication No. 61/692,076, filed Aug. 22, 2012.

BACKGROUND OF THE INVENTION

Diabetes is characterized by elevated levels of plasma glucose(hyperglycemia) in the fasting state or after administration of glucoseduring an oral glucose tolerance test. In Type 1 diabetes, orinsulin-dependent diabetes mellitus (IDDM), patients produce little orno insulin, the hormone which regulates glucose utilization. In Type 2diabetes, or noninsulin-dependent diabetes mellitus (NIDDM), insulin isstill produced by islet cells in the pancreas. Patients with Type 2diabetes have a resistance to the effects of insulin in stimulatingglucose and lipid metabolism in the main insulin-sensitive tissues,including muscle, liver and adipose tissues. These patients often havenormal levels of insulin, and may have hyperinsulinemia (elevated plasmainsulin levels), as they compensate for the reduced effectiveness ofinsulin by secreting increased amounts of insulin (Polonsky, Int. J.Obes. Relat. Metab. Disord. 24 Suppl 2:S29-31, 2000). Insulin resistanceis not primarily caused by a diminished number of insulin receptors butrather by a post-insulin receptor binding defect that is not yetcompletely understood. This lack of responsiveness to insulin results ininsufficient insulin-mediated activation of uptake, oxidation andstorage of glucose in muscle, and inadequate insulin-mediated repressionof lipolysis in adipose tissue and of glucose production and secretionin the liver. Eventually, a patient may be become diabetic due to theinability to properly compensate for insulin resistance. In humans, thebeta cells within the pancreatic islets initially compensate for insulinresistance by increasing insulin output. The onset of Type 2 diabetesdue to insufficient increases (or actual declines) in beta cell mass isapparently due to increased beta cell apoptosis relative to non-diabeticinsulin resistant individuals (Butler et al., Diabetes 52:102-110,2003).

Persistent or uncontrolled hyperglycemia is associated with increasedand premature morbidity and mortality. Often abnormal glucosehomeostasis is associated both directly and indirectly with obesity,hypertension, and alterations of the lipid, lipoprotein andapolipoprotein metabolism, as well as other metabolic and hemodynamicdisease. Patients with Type 2 diabetes mellitus have a significantlyincreased risk of macrovascular and microvascular complications,including atherosclerosis, coronary heart disease, stroke, peripheralvascular disease, hypertension, nephropathy, neuropathy, andretinopathy. Therefore, effective therapeutic control of glucosehomeostasis, lipid metabolism, obesity, and hypertension are criticallyimportant in the clinical management and treatment of diabetes mellitus.

Patients who have insulin resistance often exhibit several symptoms thattogether are referred to as Syndrome X or Metabolic Syndrome. Accordingto one widely used definition, a patient having Metabolic Syndrome ischaracterized as having three or more symptoms selected from thefollowing group of five symptoms: (1) abdominal obesity; (2)hypertriglyceridemia; (3) low high-density lipoprotein cholesterol(HDL); (4) high blood pressure; and (5) elevated fasting glucose, whichmay be in the range characteristic of Type 2 diabetes if the patient isalso diabetic. Each of these symptoms is defined clinically in the ThirdReport of the National Cholesterol Education Program Expert Panel onDetection, Evaluation and Treatment of High Blood Cholesterol in Adults(Adult Treatment Panel III, or ATP III), National Institutes of Health,2001, NIH Publication No. 01-3670. Patients with Metabolic Syndrome,whether or not they have or develop overt diabetes mellitus, have anincreased risk of developing the macrovascular and microvascularcomplications that occur with Type 2 diabetes, such as atherosclerosisand coronary heart disease.

There are several available treatments for Type 2 diabetes, each ofwhich has its own limitations and potential risks. Physical exercise anda reduction in dietary intake of calories often dramatically improve thediabetic condition and are the usual recommended first-line treatment ofType 2 diabetes and of pre-diabetic conditions associated with insulinresistance. Compliance with this treatment is generally very poorbecause of well-entrenched sedentary lifestyles and excess foodconsumption, especially of foods containing high amounts of fat andcarbohydrates. Pharmacologic treatments for diabetes have largelyfocused on three areas of pathophysiology: (1) hepatic glucoseproduction (biguanides, such as phenformin and metformin), (2) insulinresistance (PPAR agonists, such as rosiglitazone, troglitazone,engliazone, balaglitazone, MCC-555, netoglitazone, T-131, LY-300512,LY-818 and pioglitazone), (3) insulin secretion (sulfonylureas, such astolbutamide, glipizide and glimipiride); (4) incretin hormone mimetics(GLP-1 derivatives and analogs, such as exenatide and liraglutide); and(5) inhibitors of incretin hormone degradation (DPP-4 inhibitors, suchas sitagliptin).

Many of the current treatments for diabetes have unwanted side effects.Phenformin and metformin can induce lactic acidosis, nausea/vomiting,and diarrhea. Metformin has a lower risk of side effects than phenforminand is widely prescribed for the treatment of Type 2 diabetes. Thecurrently marketed PPAR gamma agonists are modestly effective inreducing plasma glucose and hemoglobinA1C, and do not greatly improvelipid metabolism or the lipid profile. Sulfonylureas and related insulinsecretagogues can cause insulin secretion even if the glucose level islow, resulting in hypoglycemia, which can be fatal in severe cases. Theadministration of insulin secretagogues must therefore be carefullycontrolled. There remains a need for treatments for diabetes that workby novel mechanisms of action and that exhibit fewer side effects.

AMP-activated protein kinase (AMPK) has been identified as a regulatorof carbohydrate and fatty acid metabolism that helps maintain energybalance in response to environmental and nutritional stress. There isevidence that activation of AMPK results in a number of beneficialeffects on lipid and glucose metabolism by reducing glucogenesis and denovo lipogenesis (fatty acid and cholesterol synthesis), and byincreasing fatty acid oxidation and skeletal muscle glucose uptake.Inhibition of ACC, by phosphorylation by AMPK, leads to a decrease infatty acid synthesis and to an increase in fatty acid oxidation, whileinhibition of HMG-CoA reductase, by phosphorylation by AMPK, leads to adecrease in cholesterol synthesis (Carling, D. et. al., FEBS Letters223:217 (1987)).

In the liver, AMPK activation results in a decrease in fatty acid andcholesterol synthesis, inhibiting hepatic glucose production andincreasing fatty acid oxidation. It has been shown that AMP-activatedprotein kinase regulates triacylglycerol synthesis and fatty acidoxidation in liver and muscle via glycerol-3-phosphate acyltransferase(Muoio, D. M. et. al., Biochem. J. 338:783 (1999)). Another substrace ofAMPK, hepatocyte nuclear factor-4α, has been shown to be involved intype-1 maturity onset diabetes (Leclerc, I. et. al., Diabetes 50:1515(2001)). Additional processes believed to be regulated through AMPKactivation include the stimulation of glucose transport in skeletalmuscle and the regulation of key genes in fatty acid and glucosemetabolism in the liver (Hardie, D. G. and Hawley, S. A., Bioessays 23:1112 (2001), Kemp, B. E. et. al., Biochem. Soc. Transactions 31:162(2003), Musi, N. and Goodyear, L. J. Current Drug Targets-Immune,Endocrine and Metabolic Disorders 2:119 (2002); Lochhead, P. A. et. al.,Diabetes 49:896 (2000); and Zhou, G. et. al., J. of Clin. Invest. 108:1167 (2001).

In vivo studies have demonstrated the following beneficial effects ofboth acute and chronic administration of AICAR, an AMPK activator, inrodent models of obesity and type 2 diabetes: 1) an improvement inglucose homeostasis in insulin-resistant diabetic (ob/ob) mice; 2) adecrease in blood glucose concentrations in ob/ob and db/db mice and ablood glucose reduction of 35% following 8 weeks of administration; and3) a reduction in metabolic disturbances and a reduction of bloodpressure in rats displaying characteristics of insulin resistancesyndrome (Bergeron, R. et. al., Diabetes 50:1076 (2001); Song, S. M. et.al., Diabetologia 45:56 (2002); Halseth, A. E. et. al., Biochem. andBiophys. Res. Comm. 294:798 (2002); and Buhl, E. S. et. al., Diabetes51: 2199 (2002)). A further study of 7 week AICAR administration inobese Zucker (fa/fa) rats lead to a reduction in plasma triglyceridesand free fatty acids; an increase in HDL cholesterol; and anormalization of glucose metabolism as assessed by an oral glucosetolerance test (Minokoshi, Y. et. al., Nature 415: 339 (2002)).Expression of dominant negative AMPK in skeletal muscle of transgenicmice has demonstrated that the AICAR effect on stimulation of glucosetransport is dependent on AMPK activation (Mu, J. et. al., MolecularCell 7: 1085 (2001)).

Recent data also suggest that AMPK activation is involved in the glucoseand lipid-lowering effects of the anti-diabetic drug metformin. It hasbeen shown that the diabetes drug metformin can activate AMPK in vivo athigh concentrations (Zhou, G. et. al., J. of Clin. Invest. 108: 1167(2001); Musi, N. et. al. Diabetes 51: 2074 (2002)).

Based on these studies, it is expected that the in vivo activation ofAMPK in the liver may result in the reduction of hepatic glucose output,an improvement in overall glucose homeostasis, a decrease in fatty acidand cholesterol synthesis, and an increase in fatty acid oxidation.Stimulation of AMPK in skeletal muscle is expected to result in anincrease in glucose uptake and fatty acid oxidation with resultingimprovement of glucose homeostasis, and an improvement in insulinaction. Finally, the resulting increase in energy expenditure may leadto a decrease in body weight. The lowering of blood pressure has alsobeen reported to be a consequence of AMPK activation.

Increased fatty acid synthesis is a characteristic of many tumor cells,therefore decreasing the synthesis of fatty acids via AMPK activationmay also be useful as a cancer therapy. Activation of AMPK may also beuseful to treat ischemic events in the brain (Blazquez, C. et. al., J.Neurochem. 73: 1674 (1999)); to prevent damage from reactive oxygenspecies (Zhou, M. et. al., Am. J. Physiol. Endocrinol. Metab. 279: E622(2000)); and to improve local circulatory systems (Chen, Z.-P., et. al.AMP-activated protein kinase phosphorylation of endothelial NO synthase.FEBS Letters 443: 285 (1999)).

Compounds that activate AMPK may be useful to treat type 2 diabetesmellitus, obesity, hypertension, dyslipidemia, cancer, and metabolicsyndrome, as well as cardiovascular diseases, such as myocardialinfarction and stroke, by improving glucose and lipid metabolism and byreducing body weight. There is a need for potent AMPK activators thathave pharmacokinetic and pharmacodynamic properties suitable for use ashuman pharmaceuticals.

Benzimidazole compounds are disclosed in WO 2010/051206; WO 2010/051176;WO 2010/047982; WO 2010/036613; WO 93/07124; WO 95/29897; WO 98/39342;WO 98/39343; WO 00/03997; WO 00/14095; WO 01/53272; WO 01/53291; WO02/092575; WO 02/40019; WO 03/018061; WO 05/002520; WO 05/018672; WO06/094209; U.S. Pat. No. 6,312,662; U.S. Pat. No. 6,489,476; US2005/0148643; DE 3 316 095; JP 6 298 731; EP 0 126 030; EP 0 128 862; EP0 129 506; and EP 0 120 403. AMPK activators are disclosed in WO08/006432; WO 05/051298; WO 05/020892; US 2007/015665; US 2007/032529;US 2006/287356; and US 2005/038068. Azabenzimidazole compounds aredisclosed in WO 2012/33149.

SUMMARY OF THE INVENTION

The present invention is concerned with novel benzimidazole derivativesof structural Formula I:

and pharmaceutically acceptable salts thereof. The compounds ofstructural formula I, and salts thereof, are activators of AMP-activatedprotein kinase (AMPK) and are useful in the treatment, prevention andsuppression of diseases, disorders and conditions mediated by activationof AMP-activated protein kinase. As AMPK activators, the compounds ofstructural formula I may be useful to treat Type 2 diabetes mellitus,insulin resistance, hyperglycemia, dyslipidemia, lipid disorders,obesity, hypertension, Metabolic Syndrome and atherosclerosis.

The present invention also relates to pharmaceutical compositionscomprising the compounds of the present invention and a pharmaceuticallyacceptable carrier. The present invention also relates to methods forthe treatment, control or prevention of disorders, diseases, andconditions that are responsive to activation of AMP-activated proteinkinase in a subject in need thereof by administering the compounds andpharmaceutical compositions of the present invention. The presentinvention also relates to the use of compounds of the present inventionfor manufacture of a medicament useful in treating diseases, disordersand conditions are responsive to the activation of AMP-activated proteinkinase. The present invention is also concerned with treatment of thesediseases, disorders and conditions by administering the compounds of thepresent invention in combination with a therapeutically effective amountof another agent useful to treat the disease, disorder and condition.The invention is further concerned with processes for preparing thecompounds of this invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is concerned with novel compounds of structuralFormula I:

or a pharmaceutically acceptable salt thereof, wherein:T is CR³;U is CR¹;V is CR²;W is CR⁴;X is selected from:

-   -   (1) —CH₂—,    -   (2) —CHF—,    -   (3) —CF₂—,    -   (4) —S—,    -   (5) —O—,    -   (6) —O—CH₂—,    -   (7) —O—CH₂CH₂—,    -   (8) —NH—,    -   (9) —C(O)—,    -   (10) —NHC(O)—,    -   (11) —C(O)NH—,    -   (12) —NHSO₂—,    -   (13) —SO₂NH—, and    -   (14) —CO₂—,        wherein each CH₂ is unsubstituted or substituted with 1 or 2        substituents selected from: hydroxy, halogen, NH₂, C₁₋₆alkyl,        CO₂H, CO₂C₁₋₆alkyl, COC₁₋₆alkyl, phenyl and —CH₂phenyl, and        wherein each NH is unsubstituted or substituted with 1        substituent selected from: C₁₋₆alkyl, CO₂H, CO₂C₁₋₆alkyl,        COC₁₋₆alkyl, phenyl and —CH₂phenyl;        Y is selected from:

wherein Y is unsubstituted or substituted with 1, 2, 3, 4 or 5substituents selected from R^(b);Z is selected from:

-   -   (1) NR⁵,    -   (2) —S—, and    -   (3) —O—;        each R¹ and R² is independently selected from:    -   (1) hydrogen,    -   (2) halogen,    -   (3) CN,    -   (4) CF₃,    -   (5) —C₁₋₆alkyl,    -   (6) —C₂₋₆alkenyl,    -   (7) —C₂₋₆alkynyl,    -   (8) —(CH₂)_(p)C₃₋₁₀cycloalkyl,    -   (9) —(CH₂)_(p)C₃₋₇cycloalkyl-aryl,    -   (10) —(CH₂)_(p)C₃₋₇cycloalkyl-heteroaryl,    -   (11) —(CH₂)_(p)C₄₋₁₀cycloalkenyl,    -   (12) —(CH₂)_(p)C₄₋₇cycloalkenyl-aryl,    -   (13) —(CH₂)_(p)C₄₋₇cycloalkenyl-heteroaryl,    -   (14) —(CH₂)_(p)C₂₋₁₀cycloheteroalkyl,    -   (15) —(CH₂)_(p)C₂₋₁₀cycloheteroalkenyl,    -   (16) —(CH₂)_(p)aryl,    -   (17) —(CH₂)_(p)aryl-C₁₋₈alkyl,    -   (18) —(CH₂)_(p)aryl-C₂₋₈alkenyl,    -   (19) —(CH₂)_(p)aryl-C₂₋₈alkynyl-C₁₋₈alkyl,    -   (20) —(CH₂)_(p)aryl-C₂₋₈alkynyl-C₃₋₇cycloalkyl,    -   (21) —(CH₂)_(p)aryl-C₂₋₈alkynyl-C₃₋₇cycloalkenyl,    -   (22) —(CH₂)_(p)aryl-C₂₋₈alkynyl-C₂₋₁₀cycloheteroalkyl,    -   (23) —(CH₂)_(p)aryl-C₂₋₈alkynyl-C₂₋₁₀cycloheteroalkenyl,    -   (24) —(CH₂)_(p)aryl-C₂₋₈alkynyl-aryl,    -   (25) —(CH₂)_(p)aryl-C₂₋₈alkynyl-heteroaryl,    -   (26) —(CH₂)_(p)aryl-C₃₋₇cycloalkyl,    -   (27) —(CH₂)_(p)aryl-C₂₋₁₀cycloheteroalkyl,    -   (28) —(CH₂)_(p)aryl-C₂₋₁₀cycloheteroalkenyl,    -   (29) —(CH₂)_(p)aryl-aryl,    -   (30) —(CH₂)_(p)aryl-heteroaryl,    -   (31) —(CH₂)_(p)heteroaryl,    -   (32) —(CH₂)_(p)heteroaryl-C₃₋₇cycloalkyl,    -   (33) —(CH₂)_(p)heteroaryl-C₂₋₁₀cycloheteroalkyl,    -   (34) —(CH₂)_(p)heteroaryl-C₂₋₁₀cycloheteroalkenyl,    -   (35) —(CH₂)_(p)heteroaryl-aryl,    -   (36) —(CH₂)_(p)heteroaryl-heteroaryl,    -   (37) —C₂₋₆alkenyl-alkyl,    -   (38) —C₂₋₆alkenyl-aryl,    -   (39) —C₂₋₆alkenyl-heteroaryl,    -   (40) —C₂₋₆alkenyl-C₃₋₇cycloalkyl,    -   (41) —C₂₋₆alkenyl-C₃₋₇cycloalkenyl,    -   (42) —C₂₋₆alkenyl-C₂₋₇cycloheteroalkyl,    -   (43) —C₂₋₆alkenyl-C₂₋₇cycloheteroalkenyl,    -   (44) —C₂₋₆alkynyl-(CH₂)₁₋₃—O-aryl,    -   (45) —C₂₋₆alkynyl-alkyl,    -   (46) —C₂₋₆alkynyl-aryl,    -   (47) —C₂₋₆alkynyl-heteroaryl,    -   (48) —C₂₋₆alkynyl-C₃₋₇cycloalkyl,    -   (49) —C₂₋₆alkynyl-C₃₋₇cycloalkenyl,    -   (50) —C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl,    -   (51) —C₂₋₆alkynyl-C₂₋₇cycloheteroalkenyl, and    -   (52) —C(O)NH—(CH₂)₀₋₃phenyl,        wherein each CH₂ is unsubstituted or substituted with 1 or 2        substituents selected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl,        —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, wherein each        alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,        cycloheteroalkyl, cycloheteroalkenyl, phenyl, aryl and        heteroaryl is unsubstituted or substituted with 1, 2, 3 or 4        substituents independently selected from R^(a),        provided that at least one of and only one of R¹ and R² is        selected from the group consisting of: hydrogen, halogen, —CN,        —CF₃, —C₁₋₆alkyl, —C₂₋₆alkenyl and —C₂₋₆alkynyl;        R³ and R⁴ are each independently selected from:    -   (1) hydrogen,    -   (2) halogen,    -   (3) —C₁₋₆alkyl,    -   (4) —C₂₋₆alkenyl,    -   (5) —C₂₋₆alkynyl,    -   (6) —C₃₋₁₀cycloalkyl,    -   (7) —C₃₋₁₀cycloalkenyl,    -   (8) aryl,    -   (9) heteroaryl,    -   (10) —CN,    -   (11) —CF₃,    -   (12) —OH,    -   (13) —OC₁₋₆alkyl,    -   (14) —NH₂,    -   (15) —NHC₁₋₆alkyl,    -   (16) —N(C₁₋₆alkyl)₂,    -   (17) —SC₁₋₆alkyl,    -   (18) —SOC₁₋₆alkyl,    -   (19) —SO₂C₁₋₆alkyl,    -   (20) —NHSO₂C₁₋₆alkyl,    -   (21) NHC(O)C₁₋₆alkyl,    -   (22) SO₂NHC₁₋₆alkyl, and    -   (23) C(O)NHC₁₋₆alkyl;        R⁵ is selected from:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl,    -   (3) —C₁₋₆alkenyl,    -   (4) —(CH₂)OH,    -   (5) —CH₂CO₂H, and    -   (6) —CH₂CO₂C₁₋₆alkyl;        each R^(a) is independently selected from the group consisting        of:    -   (1) —(CH₂)_(m)-halogen,    -   (2) oxo,    -   (3) —(CH₂)_(m)OH,    -   (4) —(CH₂)_(m)N(R^(j))₂,    -   (5) —(CH₂)_(m)NO₂,    -   (6) —(CH₂)_(m)CN,    -   (7) —C₁₋₆alkyl,    -   (8) —(CH₂)_(m)CF₃,    -   (9) —(CH₂)_(m)OCF₃,    -   (10) —O—(CH₂)_(m)—OC₁₋₆alkyl,    -   (11) —(CH₂)_(m)N(R^(j))C(O)R^(f),    -   (12) —(CH₂)_(m)N(R^(j))CO₂R^(f),    -   (13) —(CH₂)_(m)C(═N—OH)N(R^(j))₂,    -   (14) —(CH₂)_(m)OC₁₋₆alkyl,    -   (15) —(CH₂)_(m)O—(CH₂)_(m)—C₃₋₇cycloalkyl,    -   (16) —(CH₂)_(m)O—(CH₂)_(m)—C₂₋₇cycloheteroalkyl,    -   (17) —(CH₂)_(m)O—(CH₂)_(m)-aryl,    -   (18) —(CH₂)_(m)O—(CH₂)_(m)-heteroaryl,    -   (19) —(CH₂)_(m)SC₁₋₆alkyl,    -   (20) —(CH₂)_(m)S(O)C₁₋₆alkyl,    -   (21) —(CH₂)_(m)SO₂C₁₋₆alkyl,    -   (22) —(CH₂)_(m)SO₂(CH₂)_(m)—C₃₋₇cycloalkyl,    -   (23) —(CH₂)_(m)SO₂(CH₂)_(m)—C₂₋₇cycloheteroalkyl,    -   (24) —(CH₂)_(m)SO₂(CH₂)_(m)-aryl,    -   (25) —(CH₂)_(m)SO₂(CH₂)_(m)-heteroaryl,    -   (26) —(CH₂)_(m)SO₂NH₂,    -   (27) —(CH₂)_(m)SO₂NHC₁₋₆alkyl,    -   (28) —(CH₂)_(m)SO₂NHC₃₋₇cycloalkyl,    -   (29) —(CH₂)_(m)SO₂NHC₂₋₇cycloheteroalkyl,    -   (30) —(CH₂)_(m)SO₂NH-aryl,    -   (31) —(CH₂)_(m)SO₂NH-heteroaryl,    -   (32) —(CH₂)_(m)NHSO₂C₁₋₆alkyl,    -   (33) —(CH₂)_(m)NHSO₂—C₃₋₇cycloalkyl,    -   (34) —(CH₂)_(m)NHSO₂—C₂₋₇cycloheteroalkyl,    -   (35) —(CH₂)_(m)NHSO₂-aryl,    -   (36) —(CH₂)_(m)NHSO₂NH-heteroaryl,    -   (37) —(CH₂)_(m)N(R^(j))—C₁₋₆alkyl,    -   (38) —(CH₂)_(m)N(R^(j))—C₃₋₇cycloalkyl,    -   (39) —(CH₂)_(m)N(R^(j))—C₂₋₇cycloheteroalkyl,    -   (40) —(CH₂)_(m)N(R^(j))—C₂₋₇cycloheteroalkenyl,    -   (41) —(CH₂)_(m)N(R^(j))-aryl,    -   (42) —(CH₂)_(m)N(R^(j))-heteroaryl,    -   (43) —(CH₂)_(m)C(O)R^(f),    -   (44) —(CH₂)_(m)C(O)N(R^(j))₂,    -   (45) —(CH₂)_(m)N(R^(j))C(O)N(R^(j))₂,    -   (46) —(CH₂)_(m)CO₂H,    -   (47) —(CH₂)_(m)OCOH,    -   (48) —(CH₂)_(m)CO₂R^(f),    -   (49) —(CH₂)_(m)OCOR^(f),    -   (50) —(CH₂)_(m)C₃₋₇cycloalkyl,    -   (51) —(CH₂)_(m)C₃₋₇cycloalkenyl,    -   (52) —(CH₂)_(m)C₂₋₆cycloheteroalkyl,    -   (53) —(CH₂)_(m)C₂₋₆cycloheteroalkenyl,    -   (54) —(CH₂)_(m)aryl, and    -   (55) —(CH₂)_(m)heteroaryl,        wherein each CH₂ is unsubstituted or substituted with 1 or 2        substituents selected from: oxo, —OH, —(CH₂)₁₋₃OH, —CN, —NH₂,        —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, oxo, —C₁₋₆alkyl, —C₁₋₆alkyl        substituted with 1-5 OH, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂,        —CF₃, —CO₂H, —CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl, phenyl, CH₂phenyl,        heteroaryl and CH₂heteroaryl, and wherein alkyl, cycloalkyl,        cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and        heteroaryl are unsubstituted or substituted with 1, 2, 3 or 4        substituents selected from: oxo, —OH, —(CH₂)₁₋₅OH, —(CH₂)₁₋₅CN,        —CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl,        —C₁₋₆alkyl substituted with 1-5 OH, —OC₁₋₆alkyl, halogen, —CH₂F,        —CHF₂, —CF₃, —(CH₂)₁₋₅CF₃ optionally substituted with 1, 2 or        3-OH, —CO₂H, —CO₂C₁₋₆alkyl, —SO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl,        phenyl, CH₂phenyl, heteroaryl and CH₂heteroaryl;        each R^(b) is independently selected from:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl,    -   (3) —C₁₋₆alkenyl,    -   (4) —(CH₂)_(n)C₃₋₁₀cycloalkyl,    -   (5) —(CH₂)_(n)C₃₋₁₀cycloalkenyl,    -   (6) —(CH₂)_(n)C₂₋₁₀cycloheteroalkyl,    -   (7) —(CH₂)_(n)C₂₋₁₀cycloheteroalkenyl,    -   (8) —(CH₂)_(n)aryl,    -   (9) —(CH₂)_(n)heteroaryl,    -   (10) oxo,    -   (11) —(CH₂)_(n)CF₃,    -   (12) —(CH₂)_(n)CN,    -   (13) —(CH₂)_(t)-halogen,    -   (14) —(CH₂)_(s)—OH,    -   (15) —(CH₂)_(n)NO₂,    -   (16) —(CH₂)_(n)NH₂,    -   (17) —(CH₂)_(n)NH(C₁₋₆alkyl),    -   (18) —(CH₂)_(n)N(C₁₋₆alkyl)₂,    -   (19) —(CH₂)_(n)NHCO₂H,    -   (20) —(CH₂)_(n)OC₁₋₆alkyl,    -   (21) —(CH₂)_(n)OC₁₋₆alkenyl,    -   (22) —(CH₂)_(n)COC₁₋₆alkyl,    -   (23) —(CH₂)_(n)CO₂H,    -   (24) —(CH₂)_(n)OCOH,    -   (25) —(CH₂)_(n)CO₂R^(i),    -   (26) —(CH₂)_(n)OC(O)R^(i),    -   (27) —(CH₂)_(q)C(O)N(R^(e))₂,    -   (28) —(CH₂)_(q)CO₂N(R^(e))₂,    -   (29) —(CH₂)_(n)C(O)(CH₂)_(n)N(R^(g))₂,    -   (30) —(CH₂)_(n)OC(O)(CH₂)_(n)N(R^(g))₂,    -   (31) —(CH₂)_(n)N(R^(e))C(O)C₁₋₆alkyl,    -   (32) —(CH₂)_(n)N(R^(e))SO₂R^(i),    -   (33) —(CH₂)_(n)SO₂C₁₋₆alkyl,    -   (34) —(CH₂)_(n)SO₂N(R^(e))R^(g),    -   (35) (CH₂)_(n)SO₂N(R^(e))C(O)R¹,    -   (36) (CH₂)_(n)SO₂N(R^(e))CO₂R¹,    -   (37) (CH₂)_(n)SO₂N(R^(e))CON(R^(g))₂,    -   (38) (CH₂)_(n)C(O)N(R^(e))SO₂R¹,    -   (39) (CH₂)_(n)N(R^(e))C(O)N(R^(g))₂,    -   (40) ═N(OH), and    -   (41) ═N(OC₁₋₆alkyl),        wherein each CH₂ is unsubstituted or substituted with 1 or 2        substituents selected from: —C₁₋₆alkyl, —OH, halogen and —NH₂        wherein each NH is unsubstituted or substituted with 1        substituent selected from R^(c), and wherein each alkyl,        cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl,        aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3        or 4 substituents selected from R^(c), or        wherein two R^(b) substituents and the carbon to which they are        attached may form a 3 to 6 membered cycloalkyl ring, a 3-6        membered cycloalkenyl ring, a 3-6 membered cycloheteroalkyl ring        or a 3-6 membered cycloheteroalkenyl ring, wherein the ring is        unsubstituted or substituted with 1, 2, 3 or 4 substituents        selected from R^(c);        each R^(c) is independently selected from:    -   (1) halogen,    -   (2) oxo,    -   (3) —(CH₂)_(r)OH,    -   (4) —(CH₂)_(r)N(R^(e))₂,    -   (5) —(CH₂)_(r)CN,    -   (6) —C₁₋₆alkyl,    -   (7) —CF₃,    -   (8) —C₁₋₆alkyl-OH,    -   (9) —OCH₂OC₁₋₆alkyl,    -   (10) —(CH₂)_(r)OC₁₋₆alkyl,    -   (11) —OCH₂aryl,    -   (12) —(CH₂)_(r)SC₁₋₆alkyl,    -   (13) (CH₂)_(r)C(O)R^(f),    -   (14) (CH₂)_(r)C(O)N(R^(e))₂,    -   (15) —(CH₂)_(r)CO₂H,    -   (16) —(CH₂)_(r)CO₂R^(f),    -   (17) —(CH₂)_(r)C₃₋₇cycloalkyl,    -   (18) —(CH₂)_(r)C₂₋₆cycloheteroalkyl,    -   (19) —(CH₂)_(r)aryl, and    -   (20) —(CH₂)_(r)heteroaryl,        wherein each CH₂ is unsubstituted or substituted with 1 or 2        substituents selected from: oxo, —OH, —CN, —N(R^(h))₂,        —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H,        —CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl and heteroaryl, and wherein        alkyl, cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are        unsubstituted or substituted with 1, 2, 3 or 4 substituents        selected from: oxo, —OH, —CN, —N(R^(h))₂, —C₁₋₆alkyl,        —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, —CO₂C₁-6alkyl,        —C₃₋₇cycloalkyl and heteroaryl;        each R^(e), R^(g) and R^(h) is independently selected from:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl, and    -   (3) —O—C₁₋₆alkyl,        wherein alkyl is unsubstituted or substituted with 1, 2, 3 or 4        substituents selected from: —OH, oxo, halogen, C₁₋₆alkyl,        —OC₁₋₆alkyl, —NH₂, —NH(C₁₋₆alkyl), and —N(C₁₋₆alkyl)₂;        each R^(j) is independently selected from:    -   (1) hydrogen,    -   (2) C₁₋₆alkyl,    -   (3) C₃₋₆cycloalkyl,    -   (4) —C(O)R^(i),    -   (5) —CO₂R^(i), and    -   (6) —SO₂R^(i),        wherein alkyl and cycloalkyl are unsubstituted or substituted        with 1, 2, 3 or 4 substituents selected from: —OH, oxo, halogen,        C₁₋₆alkyl, —OC₁₋₆alkyl, —NH₂, —NH(C₁₋₆alkyl), and        —N(C₁₋₆alkyl)₂;        each R^(f) and R^(i) is independently selected from:    -   (1) C₁₋₆alkyl,    -   (2) —(CH₂)_(r)C₄₋₇cycloalkyl,    -   (3) —(CH₂)_(r)C₄₋₇cycloalkenyl,    -   (4) —(CH₂)_(r)C₃₋₇cycloheteroalkyl,    -   (5) —(CH₂)_(r)C₃₋₇cycloheteroalkenyl,    -   (6) —(CH₂)_(r)aryl, and    -   (7) —(CH₂)_(r)heteroaryl,        wherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl,        cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or        substituted with 1, 2, 3 or 4 substituents selected from: oxo,        —OH, —CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl,        —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, —CO₂C₁₋₆alkyl,        —C₃₋₇cycloalkyl, and heteroaryl;        n is 0, 1, 2, 3 or 4;        m is 0, 1, 2, 3 or 4;        p is 0, 1, 2, or 3;        q is 0, 1, 2, 3 or 4;        r is 0, 1 or 2;        s is 0, 1, 2, 3 or 4;        t is 0, 1, 2, 3 or 4, and        u is 0, 1, 2, 3 or 4.

In one embodiment of the present invention, T is CR³; U is CR¹; V isCR²; and W is CR⁴. In a class of this embodiment, T is CR³; U is CR¹; Vis CR²; and W is CR⁴, wherein R³ is hydrogen or halogen. In anotherclass of this embodiment, T is CR³; U is CR¹; V is CR²; and W is CR⁴,wherein R³ is hydrogen or halogen; and R² is halogen. In another classof this embodiment, T is CR³; U is CR¹; V is CR²; and W is CR⁴, whereinR³ is hydrogen or halogen; R² is halogen; and R⁴ is hydrogen.

In another embodiment of the present invention, T is —CR³—, U is —CR¹—,V is —CR²—, and W is —CR⁴—. In a class of this embodiment, T is —CR³—,wherein R³ is hydrogen; U is —CR¹—; V is —CR²—, wherein R² is Cl; and Wis —CR⁴—, wherein R⁴ is hydrogen. In another class of this embodiment, Tis —CR³—, wherein R³ is F; U is —CR¹—; V is —CR²—, wherein R² is F; andW is —CR⁴—, wherein R⁴ is hydrogen.

In another embodiment of the present invention, T is —CR³—.

In another embodiment of the present invention, U is —CR¹—.

In another embodiment of the present invention, V is —CR²—.

In another embodiment of the present invention, W is —CR⁴—.

In another embodiment of the present invention, T is —CR³—, wherein R³is H, and V is —CR², wherein R² is Cl.

In another embodiment of the present invention, T is —CR³—, wherein R³is H, and V is —CR², wherein R² is F.

In another embodiment of the present invention, X is selected from:—CH₂—, —CHF—, —CF₂—, —S—, —O—, —O—CH₂—, —O—CH₂CH₂—, —NH—, —C(O)—,—NHC(O)—, —C(O)NH—, —NHSO₂—, —SO₂NH—, and —CO₂—, wherein each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:hydroxy, halogen, NH₂, C₁₋₆alkyl, CO₂H, CO₂C₁₋₆alkyl, phenyl and—CH₂phenyl, and wherein each NH is unsubstituted or substituted with 1substituent selected from: C₁₋₆alkyl, CO₂H, CO₂C₁₋₆alkyl, COC₁₋₆alkyl,phenyl and —CH₂phenyl.

In another embodiment of the present invention, X is selected from: —S—,—O—, and —NH—. In another embodiment of the present invention, X is —O—.In another embodiment of the present invention, X is —S—. In anotherembodiment of the present invention, X is —NH—.

In another embodiment of the present invention, Y is selected from:

wherein Y is unsubstituted or substituted with 1, 2, 3, 4 or 5substituents selected from R^(b).

In another embodiment of the present invention, Y is selected from:

wherein Y is unsubstituted or substituted with 1, 2, 3, 4 or 5substituents selected from R^(b). In a class of this embodiment, Y is:

wherein Y is unsubstituted or substituted with 1, 2 or 3 substituentsselected from R^(b). In another class of this embodiment, Y is:

wherein Y is unsubstituted or substituted with 1, 2 or 3 substituentsselected from R^(b).In another class of this embodiment, Y is:

wherein Y is unsubstituted or substituted with 1, 2 or 3 substituentsselected from R^(b). In another class of this embodiment, Y is:

wherein Y is unsubstituted or substituted with 1 or 2 substituentsselected from R^(b).

In another embodiment of the present invention, Z is selected from: NR⁵,—S—, and —O—. In a class of this embodiment, Z is NR⁵. In another classof this embodiment, Z is —S—. In another class of this embodiment, Z is—O—.

In another embodiment of the present invention, each R¹ and R² isindependently selected from: hydrogen, halogen, CN, CF₃, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —(CH₂)_(p)C₃₋₁₀cycloalkyl,—(CH₂)_(p)C₃₋₇cycloalkyl-aryl, —(CH₂)_(p)C₃₋₇cycloalkyl-heteroaryl,—(CH₂)_(p)C₄₋₁₀cycloalkenyl, —(CH₂)_(p)C₄₋₇cycloalkenyl-aryl,—(CH₂)_(p)C₄₋₇cycloalkenyl-heteroaryl, —(CH₂)_(p)C₂₋₁₀cycloheteroalkyl,—(CH₂)_(p)C₂₋₁₀cycloheteroalkenyl, —(CH₂)_(p)aryl,—(CH₂)_(p)aryl-C₁₋₈alkyl, —(CH₂)_(p)aryl-C₂₋₈alkenyl,—(CH₂)_(p)aryl-C₂₋₈alkynyl-C₁₋₈alkyl,—(CH₂)_(p)aryl-C₂₋₈alkynyl-C₃₋₇cycloalkyl,—(CH₂)_(p)aryl-C₂₋₈alkynyl-C₃₋₇cycloalkenyl,—(CH₂)_(p)aryl-C₂₋₈alkynyl-C₂₋₁₀cycloheteroalkyl,—(CH₂)_(p)aryl-C₂₋₈alkynyl-C₂₋₁₀cycloheteroalkenyl,—(CH₂)_(p)aryl-C₂₋₈alkynyl-aryl, —(CH₂)_(p)aryl-C₂₋₈alkynyl-heteroaryl,—(CH₂)_(p)aryl-C₃₋₇cycloalkyl, —(CH₂)_(p)aryl-C₂₋₁₀cycloheteroalkyl,—(CH₂)_(p)aryl-C₂₋₁₀cycloheteroalkenyl, —(CH₂)_(p)aryl-aryl,—(CH₂)_(p)aryl-heteroaryl, —(CH₂)_(p)heteroaryl,—(CH₂)_(p)heteroaryl-C₃₋₇cycloalkyl,—(CH₂)_(p)heteroaryl-C₂₋₁₀cycloheteroalkyl-(CH₂)_(p)heteroaryl-C₂₋₁₀cycloheteroalkenyl,—(CH₂)_(p)heteroaryl-aryl, —(CH₂)_(p)heteroaryl-heteroaryl,—C₂₋₆alkenyl-alkyl, —C₂₋₆alkenyl-aryl, —C₂₋₆alkenyl-heteroaryl,—C₂₋₆alkenyl-C₃₋₇cycloalkyl, —C₂₋₆alkenyl-C₃₋₇cycloalkenyl,—C₂₋₆alkenyl-C₂₋₇cycloheteroalkyl, —C₂₋₆alkenyl-C₂₋₇cycloheteroalkenyl,—C₂₋₆alkynyl-(CH₂)₁₋₃—O-aryl, —C₂₋₆alkynyl-alkyl, —C₂₋₆alkynyl-aryl,—C₂₋₆alkynyl-heteroaryl, —C₂₋₆alkynyl-C₃₋₇cycloalkyl,—C₂₋₆alkynyl-C₃₋₇cycloalkenyl, —C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl,—C₂₋₆alkynyl-C₂₋₇cycloheteroalkenyl, and —C(O)NH—(CH₂)₀₋₃phenyl, whereineach CH₂ is unsubstituted or substituted with 1 or 2 substituentsselected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl,—NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, and wherein each alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl,phenyl, aryl and heteroaryl is unsubstituted or substituted with 1, 2, 3or 4 substituents independently selected from R^(a), provided that atleast one of and only one of R¹ and R² is selected from the groupconsisting of: hydrogen, halogen, —CN, —CF₃, —C₁₋₆alkyl, —C₂₋₆alkenyland —C₂₋₆alkynyl. In a class of this embodiment, at least one of andonly one of R¹ and R² is selected from halogen. In a subclass of thisclass, at least one of and only one of R¹ and R² is selected from: F andCl.

In another embodiment of the present invention, each R¹ and R² isindependently selected from: halogen,—(CH₂)_(p)aryl-C₂₋₁₀cycloheteroalkyl, and —(CH₂)_(p)aryl-aryl, whereineach CH₂ is unsubstituted or substituted with 1 or 2 substituentsselected from: halogen, CF₃, —OH, —NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl,—NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, and wherein each cycloheteroalkyl andaryl is unsubstituted or substituted with 1, 2, 3 or 4 substituentsindependently selected from R^(a), provided that at least one of andonly one of R¹ and R² is selected from halogen. In a subclass of thisclass, at least one of and only one of R¹ and R² is selected from: F andCl.

In another embodiment of the present invention, each R¹ and R² isindependently selected from: halogen, aryl-C₂₋₁₀cycloheteroalkyl, andaryl-aryl, wherein each cycloheteroalkyl and aryl is unsubstituted orsubstituted with 1, 2, 3 or 4 substituents independently selected fromR^(a), provided that at least one of and only one of R¹ and R² isselected from halogen. In a subclass of this class, at least one of andonly one of R¹ and R² is selected from: F and Cl.

In another embodiment of the present invention, each R¹ and R² isindependently selected from: halogen, phenyl-pyrrolidine, and biphenyl,wherein each pyrrolidine and phenyl is unsubstituted or substituted with1, 2, 3 or 4 substituents independently selected from R^(a), providedthat at least one of and only one of R¹ and R² is selected from halogen.In a subclass of this class, at least one of and only one of R¹ and R²is selected from: F and Cl.

In another embodiment of the present invention, each R¹ and R² isindependently selected from: halogen and aryl-aryl, wherein each aryl isunsubstituted or substituted with 1, 2, 3 or 4 substituentsindependently selected from R^(a), provided that at least one of andonly one of R¹ and R² is selected from halogen. In a subclass of thisclass, at least one of and only one of R¹ and R² is selected from: F andCl. In another subclass of this class, R² is halogen. In anothersubclass of this class, R² is Cl.

In another embodiment of the present invention, each R¹ and R² isindependently selected from: halogen and biphenyl, wherein each phenylis unsubstituted or substituted with 1, 2, 3 or 4 substituentsindependently selected from R^(a), provided that at least one of andonly one of R¹ and R² is selected from halogen. In a subclass of thisclass, at least one of and only one of R¹ and R² is selected from: F andCl. In another subclass of this class, R² is halogen. In anothersubclass of this class, R² is Cl.

In another embodiment of the present invention, each R¹ is independentlyselected from: hydrogen, halogen, CN, CF₃, —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, —(CH₂)_(p)C₃₋₁₀cycloalkyl, —(CH₂)_(p)C₃₋₇cycloalkyl-aryl,—(CH₂)_(p)C₃₋₇cycloalkyl-heteroaryl, —(CH₂)_(p)C₄₋₁₀cycloalkenyl,—(CH₂)_(p)C₄₋₇cycloalkenyl-aryl, —(CH₂)_(p)C₄₋₇cycloalkenyl-heteroaryl,—(CH₂)_(p)C₂₋₁₀cycloheteroalkyl, —(CH₂)_(p)C₂₋₁₀cycloheteroalkenyl,—(CH₂)_(p)aryl, —(CH₂)_(p)aryl-C₁₋₈alkyl, —(CH₂)_(p)aryl-C₂₋₈alkenyl,—(CH₂)_(p)aryl-C₂₋₈alkynyl-C₁₋₈alkyl,—(CH₂)_(p)aryl-C₂₋₈alkynyl-C₃₋₇cycloalkyl,—(CH₂)_(p)aryl-C₂₋₈alkynyl-C₃₋₇cycloalkenyl,—(CH₂)_(p)aryl-C₂₋₈alkynyl-C₂₋₁₀cycloheteroalkyl,—(CH₂)_(p)aryl-C₂₋₈alkynyl-C₂₋₁₀cycloheteroalkenyl,—(CH₂)_(p)aryl-C₂₋₈alkynyl-aryl, —(CH₂)_(p)aryl-C₂₋₈alkynyl-heteroaryl,—(CH₂)_(p)aryl-C₃₋₇cycloalkyl, —(CH₂)_(p)aryl-C₂₋₁₀cycloheteroalkyl,—(CH₂)_(p)aryl-C₂₋₁₀cycloheteroalkenyl, —(CH₂)_(p)aryl-aryl,—(CH₂)_(p)aryl-heteroaryl, —(CH₂)_(p)heteroaryl,—(CH₂)_(p)heteroaryl-C₃₋₇cycloalkyl,—(CH₂)_(p)heteroaryl-C₂₋₁₀cycloheteroalkyl—(CH₂)_(p)heteroaryl-C₂₋₁₀cycloheteroalkenyl, —(CH₂)_(p)heteroaryl-aryl,—(CH₂)_(p)heteroaryl-heteroaryl, —C₂₋₆alkenyl-alkyl, —C₂₋₆alkenyl-aryl,—C₂₋₆alkenyl-heteroaryl, —C₂₋₆alkenyl-C₃₋₇cycloalkyl,—C₂₋₆alkenyl-C₃₋₇cycloalkenyl, —C₂₋₆alkenyl-C₂₋₇cycloheteroalkyl,—C₂₋₆alkenyl-C₂₋₇cycloheteroalkenyl, —C₂₋₆alkynyl-(CH₂)₁₋₃—O-aryl,—C₂₋₆alkynyl-alkyl, —C₂₋₆alkynyl-aryl, —C₂₋₆alkynyl-heteroaryl,—C₂₋₆alkynyl-C₃₋₇cycloalkyl, —C₂₋₆alkynyl-C₃₋₇cycloalkenyl,—C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl, —C₂₋₆alkynyl-C₂₋7cycloheteroalkenyl,and —C(O)NH—(CH₂)₀₋₃phenyl, wherein each CH₂ is unsubstituted orsubstituted with 1 or 2 substituents selected from: halogen, CF₃, —OH,—NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, andwherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloheteroalkyl, cycloheteroalkenyl, phenyl, aryl and heteroaryl isunsubstituted or substituted with 1, 2, 3 or 4 substituentsindependently selected from R^(a).

In another embodiment of the present invention, each R¹ is independentlyselected from: —(CH₂)_(p)C₃₋₁₀cycloalkyl, —(CH₂)_(p)C₃₋₇cycloalkyl-aryl,—(CH₂)_(p)C₃₋₇cycloalkyl-heteroaryl, —(CH₂)_(p)C₄₋₁₀cycloalkenyl,—(CH₂)_(p)C₄₋₇cycloalkenyl-aryl, —(CH₂)_(p)C₄₋₇cycloalkenyl-heteroaryl,—(CH₂)_(p)C₂₋₁₀cycloheteroalkyl, —(CH₂)_(p)C₂₋₁₀cycloheteroalkenyl,—(CH₂)_(p)aryl, —(CH₂)_(p)aryl-C₁₋₈alkyl, —(CH₂)_(p)aryl-C₂₋₈alkenyl,—(CH₂)_(p)aryl-C₂₋₈alkynyl-C₁₋₈alkyl,—(CH₂)_(p)aryl-C₂₋₈alkynyl-C₃₋₇cycloalkyl,—(CH₂)_(p)aryl-C₂₋₈alkynyl-C₃₋₇cycloalkenyl,—(CH₂)_(p)aryl-C₂₋₈alkynyl-C₂₋₁₀cycloheteroalkyl,—(CH₂)_(p)aryl-C₂₋₈alkynyl-C₂₋10cycloheteroalkenyl,—(CH₂)_(p)aryl-C₂₋₈alkynyl-aryl, —(CH₂)_(p)aryl-C₂₋₈alkynyl-heteroaryl,—(CH₂)_(p)aryl-C₃₋₇cycloalkyl, —(CH₂)_(p)aryl-C₂₋₁₀cycloheteroalkyl,—(CH₂)_(p)aryl-C₂₋₁₀cycloheteroalkenyl, —(CH₂)_(p)aryl-aryl,—(CH₂)_(p)aryl-heteroaryl, —(CH₂)_(p)heteroaryl,—(CH₂)_(p)heteroaryl-C₃₋₇cycloalkyl,—(CH₂)_(p)heteroaryl-C₂₋₁₀cycloheteroalkyl—(CH₂)_(p)heteroaryl-C₂₋₁₀cycloheteroalkenyl, —(CH₂)_(p)heteroaryl-aryl,—(CH₂)_(p)heteroaryl-heteroaryl, —C₂₋₆alkenyl-alkyl, —C₂₋₆alkenyl-aryl,—C₂₋₆alkenyl-heteroaryl, —C₂₋₆alkenyl-C₃₋₇cycloalkyl,—C₂₋₆alkenyl-C₃₋₇cycloalkenyl, —C₂₋₆alkenyl-C₂₋₇cycloheteroalkyl,—C₂₋₆alkenyl-C₂₋₇cycloheteroalkenyl, —C₂₋₆alkynyl-(CH₂)₁₋₃—O-aryl,—C₂₋₆alkynyl-alkyl, —C₂₋₆alkynyl-aryl, —C₂₋₆alkynyl-heteroaryl,—C₂₋₆alkynyl-C₃₋₇cycloalkyl, —C₂₋₆alkynyl-C₃₋₇cycloalkenyl,—C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl, —C₂₋₆alkynyl-C₂₋₇cycloheteroalkenyl,and —C(O)NH—(CH₂)₀₋₃phenyl, wherein each CH₂ is unsubstituted orsubstituted with 1 or 2 substituents selected from: halogen, CF₃, —OH,—NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, andwherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloheteroalkyl, cycloheteroalkenyl, phenyl, aryl and heteroaryl isunsubstituted or substituted with 1, 2, 3 or 4 substituentsindependently selected from R^(a).

In another embodiment of the present invention, each R¹ is independentlyselected from: —(CH₂)_(p)aryl-C₂₋₁₀cycloheteroalkyl, and—(CH₂)_(p)aryl-aryl, wherein each CH₂ is unsubstituted or substitutedwith 1 or 2 substituents selected from: halogen, CF₃, —OH, —NH₂,—C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, and whereineach cycloheteroalkyl and aryl is unsubstituted or substituted with 1,2, 3 or 4 substituents independently selected from R^(a).

In another embodiment of the present invention, each R¹ is independentlyselected from: aryl-C₂₋₁₀cycloheteroalkyl, and aryl-aryl, wherein eachcycloheteroalkyl and aryl is unsubstituted or substituted with 1, 2, 3or 4 substituents independently selected from R^(a).

In another embodiment of the present invention, each R¹ is independentlyselected from: phenyl-pyrrolidine, and biphenyl, wherein eachpyrrolidine and phenyl is unsubstituted or substituted with 1, 2, 3 or 4substituents independently selected from R^(a).

In another embodiment of the present invention, each R¹ is independentlyselected from: aryl-aryl, wherein each aryl is unsubstituted orsubstituted with 1, 2, 3 or 4 substituents independently selected fromR^(a).

In another embodiment of the present invention, each R¹ is independentlyselected from: biphenyl, wherein each phenyl is unsubstituted orsubstituted with 1, 2, 3 or 4 substituents independently selected fromR^(a).

In another embodiment of the present invention, each R¹ is independentlyselected from: hydrogen, halogen, —CN, —CF₃, —C₁₋₆alkyl, —C₂₋₆alkenyland —C₂₋₆alkynyl. In another embodiment of the present invention, eachR¹ is independently selected from: halogen. In another embodiment of thepresent invention, each R¹ is independently selected from: Cl and F. Ina class of this embodiment, R¹ is Cl. In another class of thisembodiment, R¹ is F.

In another embodiment of the present invention, R² is independentlyselected from: hydrogen, halogen, CN, CF₃, —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, —(CH₂)_(p) C₃₋₁₀cycloalkyl, —(CH₂)_(p)C₃₋₇cycloalkyl-aryl,—(CH₂)_(p)C₃₋₇cycloalkyl-heteroaryl, —(CH₂)_(p) C₄₋₁₀cycloalkenyl,—(CH₂)_(p)C₄₋₇cycloalkenyl-aryl, —(CH₂)_(p)C₄₋₇cycloalkenyl-heteroaryl,—(CH₂)_(p)C₂₋₁₀cycloheteroalkyl, —(CH₂)_(p) C₂₋₁₀cycloheteroalkenyl,—(CH₂)_(p) aryl, —(CH₂)_(p)aryl-C₁₋₈alkyl, —(CH₂)_(p)aryl-C₂₋₈alkenyl,—(CH₂)_(p)aryl-C₂₋₈alkynyl-C₁₋₈alkyl, —(CH₂)_(p)aryl-C₂₋₈alkynyl-C₃₋₇cycloalkyl,—(CH₂)_(p)aryl-C₂₋₈alkynyl-C₃₋₇cycloalkenyl,—(CH₂)_(p)aryl-C₂₋₈alkynyl-C₂₋₁₀cycloheteroalkyl, —(CH₂)_(p)aryl-C₂₋₈alkynyl-C₂₋₁₀cycloheteroalkenyl,—(CH₂)_(p)aryl-C₂₋₈alkynyl-aryl, —(CH₂)_(p)aryl-C₂₋₈alkynyl-heteroaryl,—(CH₂)_(p)aryl-C₃₋₇cycloalkyl, —(CH₂)_(p)aryl-C₂₋₁₀cycloheteroalkyl,—(CH₂)_(p)aryl-C₂₋₁₀cycloheteroalkenyl, —(CH₂)_(p)aryl-aryl,—(CH₂)_(p)aryl-heteroaryl, —(CH₂)_(p)heteroaryl,—(CH₂)_(p)heteroaryl-C₃₋₇cycloalkyl,—(CH₂)_(p)heteroaryl-C₂₋₁₀cycloheteroalkyl—(CH₂)_(p)heteroaryl-C₂₋₁₀cycloheteroalkenyl, —(CH₂)_(p)heteroaryl-aryl,—(CH₂)_(p)heteroaryl-heteroaryl, —C₂₋₆alkenyl-alkyl, —C₂₋₆alkenyl-aryl,—C₂₋₆alkenyl-heteroaryl, —C₂₋₆alkenyl-C₃₋₇cycloalkyl,—C₂₋₆alkenyl-C₃₋₇cycloalkenyl, —C₂₋₆alkenyl-C₂₋₇cycloheteroalkyl,—C₂₋₆alkenyl-C₂₋₇cycloheteroalkenyl, —C₂₋₆alkynyl-(CH₂)₁₋₃—O-aryl,—C₂₋₆alkynyl-alkyl, —C₂₋₆alkynyl-aryl, —C₂₋₆alkynyl-heteroaryl,—C₂₋₆alkynyl-C₃₋₇cycloalkyl, —C₂₋6alkynyl-C₃₋₇cycloalkenyl,—C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl, —C₂₋₆alkynyl-C₂₋₇cycloheteroalkenyl,and —C(O)NH—(CH₂)₀₋₃phenyl, wherein each CH₂ is unsubstituted orsubstituted with 1 or 2 substituents selected from: halogen, CF₃, —OH,—NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, andwherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloheteroalkyl, cycloheteroalkenyl, phenyl, aryl and heteroaryl isunsubstituted or substituted with 1, 2, 3 or 4 substituentsindependently selected from R^(a).

In another embodiment of the present invention, R² is independentlyselected from: —(CH₂)_(p)C₃₋₁₀cycloalkyl, —(CH₂)_(p)C₃₋₇cycloalkyl-aryl,—(CH₂)_(p)C₃₋₇cycloalkyl-heteroaryl, —(CH₂)_(p)C₄₋₁₀cycloalkenyl,—(CH₂)_(p)C₄₋₇cycloalkenyl-aryl, —(CH₂)_(p)C₄₋₇cycloalkenyl-heteroaryl,—(CH₂)_(p)C₂₋₁₀cycloheteroalkyl, —(CH₂)_(p)C₂₋₁₀cycloheteroalkenyl,—(CH₂)_(p)aryl, —(CH₂)_(p)aryl-C₁₋₈alkyl, —(CH₂)_(p)aryl-C₂₋₈alkenyl,—(CH₂)_(p)aryl-C₂₋₈alkynyl-C₁₋₈alkyl,—(CH₂)_(p)aryl-C₂₋₈alkynyl-C₃₋₇cycloalkyl,—(CH₂)_(p)aryl-C₂₋₈alkynyl-C₃₋₇cycloalkenyl,—(CH₂)_(p)aryl-C₂₋₈alkynyl-C₂₋₁₀cycloheteroalkyl,—(CH₂)_(p)aryl-C₂₋₈alkynyl-C₂₋₁₀cycloheteroalkenyl,—(CH₂)_(p)aryl-C₂₋₈alkynyl-aryl, —(CH₂)_(p)aryl-C₂₋₈alkynyl-heteroaryl,—(CH₂)_(p)aryl-C₃₋₇cycloalkyl, —(CH₂)_(p)aryl-C₂₋₁₀cycloheteroalkyl,—(CH₂)_(p)aryl-C₂₋₁₀cycloheteroalkenyl, —(CH₂)_(p)aryl-aryl,—(CH₂)_(p)aryl-heteroaryl, —(CH₂)_(p)heteroaryl,—(CH₂)_(p)heteroaryl-C₃₋₇cycloalkyl,—(CH₂)_(p)heteroaryl-C₂₋₁₀cycloheteroalkyl—(CH₂)_(p)heteroaryl-C₂₋₁₀cycloheteroalkenyl, —(CH₂)_(p)heteroaryl-aryl,—(CH₂)_(p)heteroaryl-heteroaryl, —C₂₋₆alkenyl-alkyl, —C₂₋₆alkenyl-aryl,—C₂₋₆alkenyl-heteroaryl, —C₂₋₆alkenyl-C₃₋₇cycloalkyl,—C₂₋₆alkenyl-C₃₋₇cycloalkenyl, —C₂₋₆alkenyl-C₂₋₇cycloheteroalkyl,—C₂₋₆alkenyl-C₂₋₇cycloheteroalkenyl, —C₂₋₆alkynyl-(CH₂)₁₋₃—O-aryl,—C₂₋₆alkynyl-alkyl, —C₂₋₆alkynyl-aryl, —C₂₋₆alkynyl-heteroaryl,—C₂₋₆alkynyl-C₃₋₇cycloalkyl, —C₂₋₆alkynyl-C₃₋₇cycloalkenyl,—C₂₋₆alkynyl-C₂₋₇cycloheteroalkyl, —C₂₋₆alkynyl-C₂₋₇cycloheteroalkenyl,and —C(O)NH—(CH₂)₀₋₃phenyl, wherein each CH₂ is unsubstituted orsubstituted with 1 or 2 substituents selected from: halogen, CF₃, —OH,—NH₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, andwherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloheteroalkyl, cycloheteroalkenyl, phenyl, aryl and heteroaryl isunsubstituted or substituted with 1, 2, 3 or 4 substituentsindependently selected from R^(a).

In another embodiment of the present invention, each R² is independentlyselected from: —(CH₂)_(p)aryl-C₂₋₁₀cycloheteroalkyl, and—(CH₂)_(p)aryl-aryl, wherein each CH₂ is unsubstituted or substitutedwith 1 or 2 substituents selected from: halogen, CF₃, —OH, —NH₂,—C₁₋₆alkyl, —OC₁₋₆alkyl, —NHC₁₋₆alkyl, and —N(C₁₋₆alkyl)₂, and whereineach cycloheteroalkyl and aryl is unsubstituted or substituted with 1,2, 3 or 4 substituents independently selected from R^(a).

In another embodiment of the present invention, each R² is independentlyselected from: aryl-C₂₋₁₀cycloheteroalkyl, and aryl-aryl, wherein eachcycloheteroalkyl and aryl is unsubstituted or substituted with 1, 2, 3or 4 substituents independently selected from R^(a).

In another embodiment of the present invention, each R² is independentlyselected from: phenyl-pyrrolidine, and biphenyl, wherein eachpyrrolidine and phenyl is unsubstituted or substituted with 1, 2, 3 or 4substituents independently selected from R^(a).

In another embodiment of the present invention, each R² is independentlyselected from: aryl-aryl, wherein each aryl is unsubstituted orsubstituted with 1, 2, 3 or 4 substituents independently selected fromR^(a).

In another embodiment of the present invention, each R² is independentlyselected from: biphenyl, wherein each phenyl is unsubstituted orsubstituted with 1, 2, 3 or 4 substituents independently selected fromR^(a).

In another embodiment of the present invention, each R² is independentlyselected from: hydrogen, halogen, —CN, —CF₃, —C₁₋₆alkyl, —C₂₋₆alkenyland —C₂₋₆alkynyl. In another embodiment of the present invention, eachR² is independently selected from: halogen. In another embodiment of thepresent invention, each R² is independently selected from: Cl and F. Ina class of this embodiment, R² is Cl. In another class of thisembodiment, R² is F.

In another embodiment of the present invention, R³ and R⁴ are eachindependently selected from: hydrogen, halogen, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₂₋₆alkynyl, —C₃₋₁₀cycloalkyl, —C₃₋₁₀cycloalkenyl, aryl,heteroaryl, —CN, —CF₃, —OH, —OC₁₋₆alkyl, —NH₂, —NHC₁₋₆alkyl,—N(C₁₋₆alkyl)₂, —SC₁₋₆alkyl, —SOC₁₋₆alkyl, —SO₂C₁₋₆alkyl,—NHSO₂C₁₋₆alkyl, —NHC(O)C₁₋₆alkyl, —SO₂NHC₁₋₆alkyl, and—C(O)NHC₁₋₆alkyl.

In another embodiment of the present invention, R³ and R⁴ are eachindependently selected from: hydrogen and halogen. In a class of thisembodiment, R³ and R⁴ are each independently selected from: hydrogen, Cland F. In another class of this embodiment, R³ and R⁴ are eachindependently selected from: hydrogen and Cl. In another class of thisembodiment, R³ and R⁴ are each independently selected from: hydrogen andF. In another class of this embodiment, R³ and R⁴ are hydrogen. Inanother class of this embodiment, R³ and R⁴ are Cl. In another class ofthis embodiment, R³ and R⁴ are F.

In another embodiment of the present invention, each R³ is independentlyselected from: hydrogen, halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, —C₃₋₁₀cycloalkyl, —C₃₋₁₀cycloalkenyl, aryl, heteroaryl,—CN, —CF₃, —OH, —OC₁₋₆alkyl, —NH₂, —NHC₁₋₆alkyl, —N(C₁₋₆alkyl)₂,—SC₁₋₆alkyl, —SOC₁₋₆alkyl, —SO₂C₁₋₆alkyl, —NHSO₂C₁₋₆alkyl,—NHC(O)C₁₋₆alkyl, —SO₂NHC₁₋₆alkyl, and —C(O)NHC₁₋₆alkyl.

In another embodiment of the present invention, R³ is selected fromhydrogen, halogen, and —C₁₋₆alkyl. In a class of this embodiment, R³ ishydrogen. In a class of this embodiment, R³ is halogen.

In another embodiment of the present invention, R³ is independentlyselected from: hydrogen and halogen. In a class of this embodiment, R³is independently selected from: hydrogen, Cl and F. In another class ofthis embodiment, R³ is independently selected from: hydrogen and Cl. Inanother class of this embodiment, R³ is independently selected from:hydrogen and F. In another class of this embodiment, R³ is hydrogen. Inanother class of this embodiment, R³ is Cl. In another class of thisembodiment, R³ is F.

In another embodiment of the present invention, each R⁴ is independentlyselected from: hydrogen, halogen, —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₂₋₆alkynyl, —C₃₋₁₀cycloalkyl, —C₃₋₁₀cycloalkenyl, aryl, heteroaryl,—CN, —CF₃, —OH, —OC₁₋₆alkyl, —NH₂, —NHC₁₋₆alkyl, —N(C₁₋₆alkyl)₂,—SC₁₋₆alkyl, —SOC₁₋₆alkyl, —SO₂C₁₋₆alkyl, —NHSO₂C₁₋₆alkyl,—NHC(O)C₁₋₆alkyl, —SO₂NHC₁₋₆alkyl, and —C(O)NHC₁₋₆alkyl.

In another embodiment of the present invention, R⁴ is selected fromhydrogen, halogen, and —C₁₋₆alkyl. In a class of this embodiment, R⁴ ishydrogen. In another class of this embodiment, R⁴ is halogen.

In another embodiment of the present invention, R⁴ is independentlyselected from: hydrogen and halogen. In a class of this embodiment, R⁴is independently selected from: hydrogen, Cl and F. In another class ofthis embodiment, R⁴ is independently selected from: hydrogen and Cl. Inanother class of this embodiment, R⁴ is independently selected from:hydrogen and F. In another class of this embodiment, R⁴ is hydrogen. Inanother class of this embodiment, R⁴ is Cl. In another class of thisembodiment, R⁴ is F.

In another embodiment of the present invention, R⁵ is selected from:hydrogen, —C₁₋₆alkyl, —C₁₋₆alkenyl, —(CH₂)OH, —CH₂CO₂H, and—CH₂CO₂C₁₋₆alkyl. In a class of this embodiment, R⁵ is hydrogen.

In another embodiment of the present invention, each R^(a) isindependently selected from the group consisting of: —(CH₂)_(m)-halogen,oxo, —(CH₂)_(m)OH, —(CH₂)_(m)N(R^(j))₂, —(CH₂)_(m)NO₂, —(CH₂)_(m)CN,—C₁₋₆alkyl, —(CH₂)_(m)CF₃, —(CH₂)_(m)OCF₃, —O—(CH₂)_(m)—OC₁₋₆alkyl,—(CH₂)_(m)N(ROC(O)R^(f), —(CH₂)_(m)N(R^(j))CO₂R^(f),—(CH₂)_(m)C(═N—OH)N(R^(j))₂, —(CH₂)_(m)OC₁₋₆alkyl,—(CH₂)_(m)O—(CH₂)_(m)—C₃₋₇cycloalkyl,—(CH₂)_(m)O—(CH₂)_(m)—C₂₋₇cycloheteroalkyl, —(CH₂)_(m)O—(CH₂)_(m)-aryl,—(CH₂)_(m)O—(CH₂)_(m)-heteroaryl, —(CH₂)_(m)SC₁₋₆alkyl,—(CH₂)_(m)S(O)C₁₋₆alkyl, —(CH₂)_(m)SO₂C₁₋₆alkyl,—(CH₂)_(m)SO₂(CH₂)_(m)—C₃₋₇cycloalkyl,—(CH₂)_(m)SO₂(CH₂)_(m)—C₂₋₇cycloheteroalkyl,—(CH₂)_(m)SO₂(CH₂)_(m)-aryl, —(CH₂)_(m)SO₂(CH₂)_(m)-heteroaryl,—(CH₂)_(m)SO₂NH₂, —(CH₂)_(m)SO₂NHC₁₋₆alkyl,—(CH₂)_(m)SO₂NHC₃₋₇cycloalkyl, —(CH₂)_(m)SO₂NHC₂₋₇cycloheteroalkyl,—(CH₂)_(m)SO₂NH-aryl, —(CH₂)_(m)SO₂NH-heteroaryl,—(CH₂)_(m)NHSO₂C₁₋₆alkyl, —(CH₂)_(m)NHSO₂—C₃₋₇cycloalkyl,—(CH₂)_(m)NHSO₂—C₂₋7cycloheteroalkyl, —(CH₂)_(m)NHSO₂-aryl,—(CH₂)_(m)NHSO₂NH-heteroaryl, —(CH₂)_(m)N(R^(j))—C₁₋₆alkyl,—(CH₂)_(m)N(R^(j))—C₃₋₇cycloalkyl,—(CH₂)_(m)N(R^(j))—C₂₋₇cycloheteroalkyl,—(CH₂)_(m)N(R^(j))—C₂₋₇cycloheteroalkenyl, —(CH₂)_(m)N(R^(j))-aryl,—(CH₂)_(m)N(R^(j))-heteroaryl, —(CH₂)_(m)C(O)R^(f),—(CH₂)_(m)C(O)N(R^(j))₂, —(CH₂)_(m)N(R^(j))C(O)N(R^(j))₂,—(CH₂)_(m)CO₂H, —(CH₂)_(m)OCOH, —(CH₂)_(m)CO₂R^(f), —(CH₂)_(m)OCOR^(f),—(CH₂)_(m)C₃₋₇cycloalkyl, —(CH₂)_(m)C₃₋₇cycloalkenyl,—(CH₂)_(m)C₂₋₆cycloheteroalkyl, —(CH₂)_(m)C₂₋₆cycloheteroalkenyl,—(CH₂)_(m)aryl, and —(CH₂)_(m)heteroaryl, wherein each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:oxo, —OH, —(CH₂)₁₋₃ OH, —CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, oxo,—C₁₋₆alkyl, —C₁₋₆alkyl substituted with 1-5 OH, —OC₁₋₆alkyl, halogen,—CH₂F, —CHF₂, —CF₃, —CO₂H, —CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl, phenyl,CH₂phenyl, heteroaryl and CH₂heteroaryl, and wherein alkyl, cycloalkyl,cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroarylare unsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom: oxo, —OH, —(CH₂)₁₋₅OH, —(CH₂)₁₋₅CN, —CN, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —C₁₋₆alkyl substituted with 1-5 OH,—OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —(CH₂)₁₋₅CF₃ optionallysubstituted with 1, 2 or 3-OH, —CO₂H, —CO₂C₁₋₆alkyl, —SO₂C₁₋₆alkyl,—C₃₋₇cycloalkyl, phenyl, CH₂phenyl, heteroaryl and CH₂heteroaryl.

In another embodiment of the present invention, each R^(a) isindependently selected from the group consisting of: —(CH₂)_(m)-halogen,—(CH₂)_(m)OH, —(CH₂)_(m)CN, —(CH₂)_(m)SO₂C₁₋₆alkyl,—(CH₂)_(m)SO₂(CH₂)_(m)—C₂₋₇cycloheteroalkyl, —(CH₂)_(m)C(O)N(R^(j))₂,—(CH₂)_(m)CO₂H, —(CH₂)_(m)C₂₋6cycloheteroalkyl, and—(CH₂)_(m)heteroaryl, wherein each CH₂ is unsubstituted or substitutedwith 1 or 2 substituents selected from: oxo, —OH, —(CH₂)₁₋₃OH, —CN,—NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, oxo, —C₁₋₆alkyl, —C₁₋₆alkylsubstituted with 1-5 OH, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃,—CO₂H, —CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl, phenyl, CH₂phenyl, heteroaryl andCH₂heteroaryl, and wherein alkyl, cycloheteroalkyl and heteroaryl areunsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom: oxo, —OH, —(CH₂)₁₋₅OH, —(CH₂)₁₋₅CN, —CN, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —C₁₋₆alkyl substituted with 1-5 OH,—OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —(CH₂)₁₋₅CF₃ optionallysubstituted with 1, 2 or 3-OH, —CO₂H, —CO₂C₁₋₆alkyl, —SO₂C₁₋₆alkyl,—C₃₋₇cycloalkyl, phenyl, CH₂phenyl, heteroaryl and CH₂heteroaryl. In aclass of this embodiment, each CH₂ is unsubstituted or substituted with1 or 2 substituents selected from: oxo, —OH, —(CH₂)₁₋₃OH, —CN, —NH₂,—NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, oxo, —C₁₋₆alkyl, —C₁₋₆alkyl substitutedwith 1-5 OH, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H,—CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl, phenyl, CH₂phenyl, heteroaryl andCH₂heteroaryl, and wherein alkyl, cycloheteroalkyl, and heteroaryl areunsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom: oxo, —OH, —(CH₂)₁₋₅OH, —(CH₂)₁₋₅CN, —CN, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —C₁₋₆alkyl substituted with 1-5 OH,—OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —(CH₂)₁₋₅CF₃ optionallysubstituted with 1, 2 or 3-OH, —CO₂H, —CO₂C₁₋₆alkyl, —SO₂C₁₋₆alkyl, and—C₃₋₇cycloalkyl. In another class of this embodiment, each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:—(CH₂)₁₋₃OH and —C₁₋₆alkyl, and each alkyl, cycloheteroalkyl, andheteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents selected from: oxo, —OH, —NH₂, —C₁₋₆alkyl, —C₁₋₆alkylsubstituted with 1-5 OH, and —C₃₋₇cycloalkyl. In another class of thisembodiment, In a class of this embodiment, each CH₂ is unsubstituted orsubstituted with 1 or 2 substituents selected from: —(CH₂)₁₋₃OH and—C₁₋₆alkyl, and each alkyl, cycloheteroalkyl, and heteroaryl isunsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom: oxo, —OH, —NH₂, —C₁₋₆alkyl, —C₁-6alkyl substituted with 1-5 OH,and -cyclopropyl.

In another embodiment of the present invention, each R^(a) isindependently selected from the group consisting of: halogen,—(CH₂)_(m)OH, CN, —SO₂C₁₋₆alkyl, —SO₂C₂₋₇cycloheteroalkyl,—C(O)N(R^(j))₂, —(CH₂)_(m)CO₂H, C₂₋₆cycloheteroalkyl, and heteroaryl,wherein each CH₂ is unsubstituted or substituted with 1 or 2substituents selected from: oxo, —OH, —(CH₂)₁₋₃OH, —CN, —NH₂,—NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, oxo, —C₁₋₆alkyl, —C₁₋₆alkyl substitutedwith 1-5 OH, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H,—CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl, phenyl, CH₂phenyl, heteroaryl andCH₂heteroaryl, and wherein alkyl, cycloheteroalkyl, and heteroaryl areunsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom: oxo, —OH, —(CH₂)₁₋₅OH, —(CH₂)₁₋₅CN, —CN, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —C₁₋₆alkyl substituted with 1-5 OH,—OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —(CH₂)₁₋₅CF₃ optionallysubstituted with 1, 2 or 3-OH, —CO₂H, —CO₂C₁₋₆alkyl, —SO₂C₁₋₆alkyl, and—C₃₋₇cycloalkyl. In a class of this embodiment, each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:—(CH₂)₁₋₃OH and —C₁₋₆alkyl, and each alkyl, cycloheteroalkyl, andheteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents selected from: oxo, —OH, —NH₂, —C₁₋₆alkyl, —C₁₋₆alkylsubstituted with 1-5 OH, and —C₃₋₇cycloalkyl. In another class of thisembodiment, In a class of this embodiment, each CH₂ is unsubstituted orsubstituted with 1 or 2 substituents selected from: —(CH₂)₁₋₃OH and—C₁₋₆alkyl, and each alkyl, cycloheteroalkyl, and heteroaryl isunsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom: oxo, —OH, —NH₂, —C₁₋₆alkyl, —C₁₋₆alkyl substituted with 1-5 OH,and -cyclopropyl.

In another embodiment of the present invention, each R^(a) isindependently selected from the group consisting of: F, —OH, —C(CH₃)₂OH,—C(CH₃)(CH₂OH)₂, CN, —SO₂CH₃, —CH₂SO₂CH₃, —SO₂-piperidine, —C(O)NHCH₃,—(CH₂)₃CO₂H, morpholine, pyrrolidine, pyridine, pyrimidine, oxadiazole,oxazole, tetrazole, pyrazole, thiazole, triazole, and pyridazine,wherein each CH₂ is unsubstituted or substituted with 1 or 2substituents selected from: oxo, —OH, —(CH₂)₁₋₃OH, —CN, —NH₂,—NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, oxo, —C₁₋₆alkyl, —C₁₋₆alkyl substitutedwith 1-5 OH, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H,—CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl, phenyl, CH₂phenyl, heteroaryl andCH₂heteroaryl, and wherein alkyl, cycloheteroalkyl, and heteroaryl areunsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom: oxo, —OH, —(CH₂)₁₋₅OH, —(CH₂)₁₋₅CN, —CN, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —C₁₋₆alkyl substituted with 1-5 OH,—OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —(CH₂)₁₋₅CF₃ optionallysubstituted with 1, 2 or 3-OH, —CO₂H, —CO₂C₁₋₆alkyl, —SO₂C₁₋₆alkyl, and—C₃₋₇cycloalkyl. In a class of this embodiment, each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:—(CH₂)₁₋₃OH and —C₁₋₆alkyl, and each alkyl, cycloheteroalkyl, andheteroaryl is unsubstituted or substituted with 1, 2, 3 or 4substituents selected from: oxo, —OH, —NH₂, —C₁₋₆alkyl, —C₁₋₆alkylsubstituted with 1-5 OH, and —C₃₋₇cycloalkyl. In another class of thisembodiment, In a class of this embodiment, each CH₂ is unsubstituted orsubstituted with 1 or 2 substituents selected from: —(CH₂)₁₋₃OH and—C₁₋₆alkyl, and each alkyl, cycloheteroalkyl, and heteroaryl isunsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom: oxo, —OH, —NH₂, —C₁₋₆alkyl, —C₁₋₆alkyl substituted with 1-5 OH,and -cyclopropyl.

In another embodiment of the present invention, each R^(a) isindependently selected from the group consisting of: F, —OH, —C(CH₃)₂OH,—C(CH₃)(CH₂OH)₂, CN, —SO₂CH₃, —CH₂SO₂CH₃, —SO₂-piperidine, —C(O)NHCH₃,—(CH₂)₃CO₂H, morpholine, pyrrolidine, pyridine, pyrimidine, oxadiazole,oxazole, tetrazole, pyrazole, thiazole, triazole, and pyridazine.

In another embodiment of the present invention, each R^(a) isindependently selected from the group consisting of: —(CH₂)_(m)OH,—(CH₂)_(m)SO₂C₁₋₆alkyl, —(CH₂)_(m)C(O)N(R^(j))₂,—(CH₂)_(m)C₂₋₆cycloheteroalkyl, and —(CH₂)_(m)heteroaryl, wherein eachCH₂ is unsubstituted or substituted with 1 or 2 substituents selectedfrom: oxo, —OH, —(CH₂)₁₋₃OH, —CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂,oxo, —C₁₋₆alkyl, —C₁₋₆alkyl substituted with 1-5 OH, —OC₁₋₆alkyl,halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, —CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl,phenyl, CH₂phenyl, heteroaryl and CH₂heteroaryl, and wherein alkyl,cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl andheteroaryl are unsubstituted or substituted with 1, 2, 3 or 4substituents selected from: oxo, —OH, —(CH₂)₁₋₅OH, —(CH₂)₁₋₅CN, —CN,—NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —C₁₋₆alkyl substitutedwith 1-5 OH, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —(CH₂)₁₋₅CF₃optionally substituted with 1, 2 or 3-OH, —CO₂H, —CO₂C₁₋₆alkyl,—SO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl, phenyl, CH₂phenyl, heteroaryl andCH₂heteroaryl.

In another embodiment of the present invention, each R^(a) isindependently selected from the group consisting of: —(CH₂)_(m)OH,—(CH₂)_(m)SO₂C₁₋₆alkyl, —C(O)N(R^(j))₂, —C₂-6cycloheteroalkyl, andheteroaryl, wherein each CH₂ is unsubstituted or substituted with 1 or 2substituents selected from: —C₁₋₆alkyl, and wherein alkyl,cycloheteroalkyl and heteroaryl are unsubstituted or substituted with 1,2, 3 or 4 substituents selected from: oxo, —OH, —(CH₂)₁₋₅OH, —NH₂, and—C₁₋₆alkyl substituted with 1-5 OH.

In another embodiment of the present invention, each R^(a) isindependently selected from the group consisting of: —C(CH₃)₂OH,—CH₂SO₂CH₃, —C(O)NHCH₃, morpholine, pyrrolidine, pyrimidine, pyrazole,thiazole, and triazole.

In another embodiment of the present invention, each R^(b) isindependently selected from: hydrogen, —C₁₋₆alkyl, —C₁₋₆alkenyl,—(CH₂)_(n)C₃₋₁₀cycloalkyl, —(CH₂)_(n)C₃₋₁₀cycloalkenyl,—(CH₂)_(n)C₂₋₁₀cycloheteroalkyl, —(CH₂)_(n)C₂₋₁₀cycloheteroalkenyl,—(CH₂)_(n)aryl, —(CH₂)_(n)heteroaryl, oxo, —(CH₂)_(n)CF₃, —(CH₂)_(n)CN,—(CH₂)_(t)-halogen, —(CH₂)_(s)—OH, —(CH₂)_(n)NO₂, —(CH₂)_(n)NH₂,—(CH₂)_(n)NH(C₁₋₆alkyl), —(CH₂)_(n)N(C₁₋₆alkyl)₂, —(CH₂)_(n)NHCO₂H,—(CH₂)_(n)OC₁₋₆alkyl, —(CH₂)_(n)OC₁₋₆alkenyl, —(CH₂)_(n)COC₁₋₆alkyl,—(CH₂)_(n)CO₂H, —(CH₂)_(n)OCOH, —(CH₂)_(n)CO₂R^(i),—(CH₂)_(n)OC(O)R^(i), —(CH₂)_(q)C(O)N(R^(e))₂, —(CH₂)_(q)CO₂N(R^(e))₂,—(CH₂)_(n)C(O)(CH₂)_(n)N(R^(g))₂, —(CH₂)_(n)OC(O)(CH₂)_(n)N(R^(g))₂,—(CH₂)_(n)N(R^(e))C(O)C₁₋₆alkyl, —(CH₂)_(n)N(R^(e))SO₂R^(i),—(CH₂)_(n)SO₂C₁₋₆alkyl, —(CH₂)_(n)SO₂N(R^(e))R^(g),—(CH₂)_(n)SO₂N(R^(e))C(O)R^(i), —(CH₂)_(n)SO₂N(R^(e))CO₂R^(i),—(CH₂)_(n)SO₂N(R^(e))CON(R^(g))₂, —(CH₂)_(n)C(O)N(R^(e))SO₂R^(i),—(CH₂)_(n)N(R^(e))C(C)N(R^(g))₂, ═N(OH), and ═N(OC₁₋₆alkyl), whereineach CH₂ is unsubstituted or substituted with 1 or 2 substituentsselected from: —C₁₋₆alkyl, —OH, halogen and —NH₂ wherein each NH isunsubstituted or substituted with 1 substituent selected from R^(c), andwherein each alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl,cycloheteroalkenyl, aryl and heteroaryl is unsubstituted or substitutedwith 1, 2, 3 or 4 substituents selected from R^(c), or wherein two R^(b)substituents and the carbon to which they are attached may form a 3 to 6membered cycloalkyl ring, a 3-6 membered cycloalkenyl ring, a 3-6membered cycloheteroalkyl ring or a 3-6 membered cycloheteroalkenylring, wherein the ring is unsubstituted or substituted with 1, 2, 3 or 4substituents selected from R^(c). In a class of this embodiment, twoR^(b) substituents and the carbon to which they are attached may form a3-6 membered cycloheteroalkyl ring, wherein the ring is unsubstituted orsubstituted with 1, 2, 3 or 4 substituents selected from R^(c).

In another embodiment of the present invention, each R^(b) isindependently selected from: —(CH₂)_(s)—OH, wherein each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:—C₁₋₆alkyl, —OH, halogen and —NH₂ wherein each NH is unsubstituted orsubstituted with 1 substituent selected from R^(c).

In another embodiment of the present invention, each R^(b) isindependently selected from: —OH, and —CH₂OH, wherein each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:—C₁₋₆alkyl, —OH, halogen and —NH₂ wherein each NH is unsubstituted orsubstituted with 1 substituent selected from R^(c).

In another embodiment of the present invention, each R^(b) isindependently selected from: —OH, and —CH₂OH.

In another embodiment of the present invention, each R^(b) isindependently selected from: —(CH₂)_(s)—OH, wherein each CH₂ isunsubstituted or substituted with 1 or 2 substituents selected from:—C₁₋₆alkyl, —OH, halogen and —NH₂ wherein each NH is unsubstituted orsubstituted with 1 substituent selected from R^(c).

In another embodiment of the present invention, each R^(b) isindependently selected from: —(CH₂)_(s)—OH.

In another embodiment of the present invention, each R^(b) isindependently selected from —OH and —CH₂OH.

In another embodiment of the present invention, each R^(c) isindependently selected from: halogen, oxo, —(CH₂)_(r)OH,—(CH₂)_(r)N(R^(e))₂, —(CH₂)_(r)CN, —C₁₋₆alkyl, —CF₃, —C₁₋₆alkyl-OH,—OCH₂OC₁₋₆alkyl, —(CH₂)_(r)OC₁₋₆alkyl, —OCH₂aryl, —(CH₂)_(r)SC₁₋₆alkyl,—(CH₂)_(r)C(O)R^(f), —(CH₂)_(r)C(O)N(R^(e))₂, —(CH₂)_(r)CO₂H,—(CH₂)_(r)CO₂R^(f), —(CH₂)_(r)C₃₋₇cycloalkyl,—(CH₂)_(r)C₂-6cycloheteroalkyl, —(CH₂)_(r)aryl, and—(CH₂)_(r)heteroaryl, wherein each CH₂ is unsubstituted or substitutedwith 1 or 2 substituents selected from: oxo, —OH, —CN, —N(R^(h))₂,—C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H,—CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl and heteroaryl, and wherein alkyl,cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted orsubstituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN,—N(R^(h))₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H,—CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl and heteroaryl. In a class of thisembodiment, each R^(c) is independently selected from: oxo,—(CH₂)_(r)OH, —(CH₂)_(r)CO₂H, and —(CH₂)_(r)CO₂R^(f), wherein each CH₂is unsubstituted or substituted with 1 or 2 substituents selected from:oxo, —OH, —CN, —N(R^(h))₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F,—CHF₂, —CF₃, —CO₂H, —CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl and heteroaryl. In asubclass of this class, each R^(c) is independently selected from: oxo,—OH, —CO₂H and —CO₂R^(f).

In another embodiment of the present invention, each R^(c) isindependently selected from: halogen, oxo, —(CH₂)_(r)OH,—(CH₂)_(r)N(R^(e))₂, —(CH₂)_(r)CN, —C₁₋₆alkyl, —CF₃, —C₁₋₆alkyl-OH,—OCH₂OC₁₋₆alkyl, —(CH₂)_(r)OC₁₋₆alkyl, —OCH₂aryl, —(CH₂)_(r)SC₁₋₆alkyl,—(CH₂)_(r)C(O)R^(f), —(CH₂)_(r)C(O)N(R^(e))₂, —(CH₂)_(r)CO₂H, and—(CH₂)_(r)CO₂R^(f), wherein each CH₂ is unsubstituted or substitutedwith 1 or 2 substituents selected from: oxo, —OH, —CN, —N(R^(h))₂,—C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H,—CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl and heteroaryl, and wherein alkyl,cycloalkyl, cycloheteroalkyl, aryl and heteroaryl are unsubstituted orsubstituted with 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN,—N(R^(h))₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H,and —CO₂C₁₋₆alkyl.

In another embodiment of the present invention, each R^(c) isindependently selected from: halogen, oxo, —(CH₂)_(r)OH,—(CH₂)_(r)N(R^(e))₂, —(CH₂)_(r)CN, —C₁₋₆alkyl, —CF₃, and —C₁₋₆alkyl-OH.

In another embodiment of the present invention, each R^(c) isindependently selected from: halogen, oxo, and —C₁₋₆alkyl.

In another embodiment of the present invention, each R^(e), R^(g) andR^(h) is independently selected from: hydrogen, —C₁₋₆alkyl, and—O—C₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with 1, 2, 3or 4 substituents selected from: —OH, oxo, halogen, C₁₋₆alkyl,—OC₁₋₆alkyl, —NH₂, —NH(C₁₋₆alkyl), and —N(C₁₋₆alkyl)₂.

In another embodiment of the present invention, each R^(c) isindependently selected from: hydrogen, —C₁₋₆alkyl, and —O—C₁₋₆alkyl,wherein alkyl is unsubstituted or substituted with 1, 2, 3 or 4substituents selected from: —OH, oxo, halogen, C₁₋₆alkyl, —OC₁₋₆alkyl,—NH₂, —NH(C₁₋₆alkyl), and —N(C₁₋₆alkyl)₂.

In another embodiment of the present invention, each R^(g) isindependently selected from: hydrogen, —C₁₋₆alkyl, and —O—C₁₋₆alkyl,wherein alkyl is unsubstituted or substituted with 1, 2, 3 or 4substituents selected from: —OH, oxo, halogen, C₁₋₆alkyl, —OC₁₋₆alkyl,—NH₂, —NH(C₁₋₆alkyl), and —N(C₁₋₆alkyl)₂.

In another embodiment of the present invention, each R^(h) isindependently selected from: hydrogen, —C₁₋₆alkyl, and —O—C₁₋₆alkyl,wherein alkyl is unsubstituted or substituted with 1, 2, 3 or 4substituents selected from: —OH, oxo, halogen, C₁₋₆alkyl, —OC₁₋₆alkyl,—NH₂, —NH(C₁₋₆alkyl), and —N(C₁₋₆alkyl)₂.

In another embodiment of the present invention, each R^(j) isindependently selected from: hydrogen, —C₁₋₆alkyl, —C₃₋₆cycloalkyl,—C(O)R^(i), —CO₂R^(i), and —SO₂R^(i), wherein alkyl and cycloalkyl areunsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom: —OH, oxo, halogen, C₁₋₆alkyl, —OC₁₋₆alkyl, —NH₂, —NH(C₁₋₆alkyl),and —N(C₁₋₆alkyl)₂.

In another embodiment of the present invention, each R^(j) isindependently selected from: hydrogen, and C₁₋₆alkyl, wherein alkyl isunsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom: —OH, oxo, halogen, C₁₋₆alkyl, —OC₁₋₆alkyl, —NH₂, —NH(C₁₋₆alkyl),and —N(C₁₋₆alkyl)₂. In a class of this embodiment, each R^(j) isindependently selected from: hydrogen, and —CH₃.

In another embodiment of the present invention, each R^(f) and R^(i) isindependently selected from: —C₁₋₆alkyl, —(CH₂)_(r)C₄₋₇cycloalkyl,—(CH₂)_(r)C₄₋₇cycloalkenyl, —(CH₂)_(r)C₃₋₇cycloheteroalkyl,—(CH₂)_(r)C₃₋₇cycloheteroalkenyl, —(CH₂)_(r)aryl, and—(CH₂)_(r)heteroaryl, wherein alkyl, cycloalkyl, cycloalkenyl,cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl areunsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom: oxo, —OH, —CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl,—OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, —CO₂C₁₋₆alkyl,—C₃₋₇cycloalkyl, and heteroaryl. In a class of this embodiment, alkyl,cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl andheteroaryl are unsubstituted or substituted with 1, 2, 3 or 4substituents selected from: oxo, —OH, —CN, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃,—CO₂H, and —CO₂C₁₋₆alkyl. In another class of this embodiment, eachR^(f) and R^(i) is independently selected from: —C₁₋₆alkyl, whereinalkyl is unsubstituted or substituted with 1, 2, 3 or 4 substituentsselected from: oxo, —OH, —CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂,—C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, and—CO₂C₁₋₆alkyl. In another class of this embodiment, each R^(f) and R^(i)is independently selected from: —C₁₋₆alkyl.

In another embodiment of the present invention, each R^(f) isindependently selected from: —C₁₋₆alkyl, —(CH₂)_(r)C₄₋₇cycloalkyl,—(CH₂)_(r)C₄₋₇cycloalkenyl, —(CH₂)_(r)C₃₋₇cycloheteroalkyl,—(CH₂)_(r)C₃₋₇cycloheteroalkenyl, —(CH₂)_(r)aryl, and—(CH₂)_(r)heteroaryl, wherein alkyl, cycloalkyl, cycloalkenyl,cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl areunsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom: oxo, —OH, —CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl,—OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, —CO₂C₁₋₆alkyl,—C₃₋₇cycloalkyl, and heteroaryl. In a class of this embodiment, alkyl,cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl andheteroaryl are unsubstituted or substituted with 1, 2, 3 or 4substituents selected from: oxo, —OH, —CN, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃,—CO₂H, and —CO₂C₁₋₆alkyl. In another class of this embodiment, eachR^(f) is independently selected from: —C₁₋₆alkyl, wherein alkyl isunsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom: oxo, —OH, —CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl,—OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, and —CO₂C₁₋₆alkyl. Inanother class of this embodiment, each R^(f) is independently selectedfrom: —C₁₋₆alkyl.

In another embodiment of the present invention, each R^(i) isindependently selected from: —C₁₋₆alkyl, —(CH₂)_(r)C₄₋₇cycloalkyl,—(CH₂)_(r)C₄₋₇cycloalkenyl, —(CH₂)_(r)C₃₋₇cycloheteroalkyl,—(CH₂)_(r)C₃₋₇cycloheteroalkenyl, —(CH₂)_(r)aryl, and—(CH₂)_(r)heteroaryl, wherein alkyl, cycloalkyl, cycloalkenyl,cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroaryl areunsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom: oxo, —OH, —CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl,—OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, —CO₂C₁₋₆alkyl,—C₃₋₇cycloalkyl, and heteroaryl. In a class of this embodiment, alkyl,cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl andheteroaryl are unsubstituted or substituted with 1, 2, 3 or 4substituents selected from: oxo, —OH, —CN, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃,—CO₂H, and —CO₂C₁₋₆alkyl. In another class of this embodiment, eachR^(i) is independently selected from: —C₁₋₆alkyl, wherein alkyl isunsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom: oxo, —OH, —CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl,—OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, and —CO₂C₁₋₆alkyl. Inanother class of this embodiment, each R^(i) is independently selectedfrom: —C₁₋₆alkyl.

In another embodiment of the present invention, n is 0, 1, 2, 3 or 4. Ina class of this embodiment, n is 1, 2 or 3. In another class of thisembodiment, n is 0, 1 or 2. In another class of this embodiment, n is 0.In another class of this embodiment, n is 1. In another class of thisembodiment, n is 2.

In another embodiment of the present invention, m is 0, 1, 2, 3, or 4.In a class of this embodiment, m is 0, 1, 2 or 3. In another class ofthis embodiment, m is 1, 2 or 3. In another class of this embodiment, mis 0, 1 or 2. In another class of this embodiment, m is 0 or 1. Inanother class of this embodiment, m is 0. In another class of thisembodiment, m is 1.

In another embodiment of the present invention, p is 0, 1, 2 or 3. In aclass of this embodiment, p is 1, 2 or 3. In another class of thisembodiment, p is 0, 1 or 2. In another class of this embodiment, p is 0or 2. In another class of this embodiment, p is 0. In another class ofthis embodiment, p is 1. In another class of this embodiment, p is 2.

In another embodiment of the present invention, q is 0, 1, 2, 3 or 4. Ina class of this embodiment, q is 1, 2 or 3. In another class of thisembodiment, q is 0, 1 or 2. In another class of this embodiment, q is 1or 2. In another class of this embodiment, q is 0. In another class ofthis embodiment, q is 1. In another class of this embodiment, q is 2.

In another embodiment of the present invention, r is 0, 1 or 2. In aclass of this embodiment, r is 0 or 1. In another class of thisembodiment, r is 0. In another class of this embodiment, r is 1. Inanother class of this embodiment, r is 2.

In another embodiment of the present invention, s is 0, 1, 2, 3 or 4. Ina class of this embodiment, s is 0, 1, 2 or 3. In a class of thisembodiment, s is 0, 1 or 2. In another class of this embodiment, s is 0or 1. In another class of this embodiment, s is 1 or 2. In another classof this embodiment, s is 0 or 2. In another class of this embodiment, sis 0. In another class of this embodiment, s is 1. In another class ofthis embodiment, s is 2. In another class of this embodiment, s is 3.

In another embodiment of the present invention, t is 0, 1, 2, 3 or 4. Ina class of this embodiment, t is 0, 1, 2 or 3. In a class of thisembodiment, t is 0, 1 or 2. In another class of this embodiment, t is 0or 1. In another class of this embodiment, t is 1 or 2. In another classof this embodiment, t is 0 or 2. In another class of this embodiment, tis 0. In another class of this embodiment, t is 1. In another class ofthis embodiment, t is 2. In another class of this embodiment, t is 3.

In another embodiment of the present invention, u is 0, 1, 2, 3 or 4. Ina class of this embodiment, u is 0, 1, 2 or 3. In a class of thisembodiment, u is 0, 1 or 2. In another class of this embodiment, u is 0or 1. In another class of this embodiment, u is 1 or 2. In another classof this embodiment, u is 0 or 2. In another class of this embodiment, uis 0. In another class of this embodiment, u is 1. In another class ofthis embodiment, u is 2. In another class of this embodiment, u is 3. Inanother class of this embodiment, u is 4.

Another embodiment of the present invention relates to compounds ofstructural formula I wherein:

T is CR³;

U is CR¹;

V is CR²;

W is CR⁴;

X is —O—;

Y is:

wherein Y is unsubstituted or substituted with 1, 2, 3, 4 or 5substituents selected from R^(b);Z is NR⁵;each R¹ is independently selected from:

-   -   (1) aryl-C₂₋₁₀cycloheteroalkyl, and    -   (2) aryl-aryl,        wherein each cycloheteroalkyl and aryl is unsubstituted or        substituted with 1, 2, 3 or 4 substituents independently        selected from R^(a);        R² is halogen;        R³ is hydrogen or halogen;        R⁴ is hydrogen; and        R⁵ is hydrogen;        or a pharmaceutically acceptable salt thereof

Another embodiment of the present invention relates to compounds ofstructural formula I wherein:

T is CR³;

U is CR¹;

V is CR²;

W is CR⁴;

X is —O—;

Y is:

wherein Y is unsubstituted or substituted with 1, 2 or 3 substituentsselected from R^(b);Z is NR⁵;each R¹ is independently selected from: aryl-aryl, wherein each aryl isunsubstituted or substituted with 1, 2, 3 or 4 substituentsindependently selected from R^(a);R² is halogen;R³ is hydrogen or halogen;R⁴ is hydrogen; andR⁵ is hydrogen;or a pharmaceutically acceptable salt thereof

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ia:

or a pharmaceutically acceptable salt thereof

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ib:

or a pharmaceutically acceptable salt thereof

In another embodiment of the present invention, the invention relates tocompounds of structural formula Ic:

or a pharmaceutically acceptable salt thereof

The compound of structural formula I includes the compounds ofstructural formulas Ia, Ib and Ic, and pharmaceutically acceptablesalts, hydrates and solvates thereof.

Illustrative, but non-limiting, examples of the compounds of the presentinvention that are useful as activators of AMP-protein kinase are thefollowing compounds:

and pharmaceutically acceptable salts thereof

“Alkyl”, as well as other groups having the prefix “alk”, such asalkoxy, alkanoyl, means carbon chains of up to 10 carbons which may belinear or branched or combinations thereof. Examples of alkyl groupsinclude methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec- andtert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and the like.

“Alkenyl” means carbon chains up to 10 carbons which contain at leastone carbon-carbon double bond, and which may be linear or branched orcombinations thereof. Examples of alkenyl include vinyl, allyl,isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl,2-methyl-2-butenyl, and the like. In one embodiment of the presentinvention, alkenyl is vinyl.

“Alkynyl” means carbon chains up to 10 carbons which contain at leastone carbon-carbon triple bond, and which may be linear or branched orcombinations thereof. In one embodiment, C₂₋₈alkynyl means a carbonchain with 2 to 8 carbons that contains one carbon-carbon triple bond.Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl,2-heptynyl and the like. In one embodiment of the present invention,alkynyl is ethynyl. In another embodiment, alkynyl is propargyl.

“Cycloalkyl” means mono- or bicyclic, spiro or bridged saturatedcarbocyclic rings, each having from 3 to 14 carbon atoms. Examples ofcycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, and decahydronaphthyl, and the like. In oneembodiment of the present invention, cycloalkyl is selected fromcyclopentyl and cyclohexyl. In another embodiment of the presentinvention, cycloalkyl is selected from cyclopropyl, cyclopentyl, andcyclohexyl.

“Cycloalkenyl” means nonaromatic, mono- or bicyclic, spiro or bridgedcarbocyclic rings, each having from 3 to 14 carbon atoms and containingat least one double bond. Examples of cycloalkyl include cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooxtenyl,decahydronaphthyl, bicyclo[2.2.1]hept-5-en-2-yl, and the like.

“Cycloheteroalkyl” means nonaromatic, monocyclic, bicyclic, spiro orbridged saturated carbocyclic rings, each having from 2 to 14 carbonatoms and containing 1, 2, 3, 4 or 5 heteroatoms selected from N, NH, Oand S. In one embodiment, C₂₋₁₀cycloheteroalkyl means non-aromatic,mono- or bicyclic, spiro or bridged saturated carbocyclic rings, havingfrom 2 to 10 carbon atoms and containing, 1, 2, 3, 4 or 5 heteroatomsselected from N, NH, O and S. In another embodiment,C₂₋₇cycloheteroalkyl means non-aromatic, mono- or bicyclic, spiro orbridged saturated carbocyclic rings, having from 2 to 10 carbon atomsand containing, 1, 2, 3, 4 or 5 heteroatoms selected from N, NH, O andS. In another embodiment, C₂₋₆cycloheteroalkyl means non-aromatic, mono-or bicyclic, spiro or bridged saturated carbocyclic rings, having from 2to 10 carbon atoms and containing, 1, 2, 3, 4 or 5 heteroatoms selectedfrom N, NH, O and S. Examples of cycloheteroalkyl includetetrahydrofuranyl, azetidinyl, perhydroazepinyl, dihydrofuranyl,dioxanyl, oxanyl, morpholinyl, 1,4-dithianyl, piperazinyl, piperidinyl,1,3-dioxolanyl, imidazolidinyl, imidazolinyl, pyrrolinyl, pyrrolidinyl,pyranyl, tetrahydropyranyl, dihydropyranyl, oxathiolanyl, dithiolanyl,1,3-dithianyl, oxathianyl, thiomorpholinyl, dioxidoisothiazolidinyl,azacycloheptyl, diazobicyclo[3.2.1]-octane, and hexahydroindazolyl. Thecycloheteroalkyl ring may be substituted on the ring carbons and/or thering nitrogens. In one embodiment of the present invention,cycloheteroalkyl is selected from piperidine, pyrrolidine, oxazolidine,1,3-oxazolidine-2,4-dione, thiazolidine, 1,3-thiazolidine-2,4-dione,imidazolidine, and hydantoin, and the like. In another embodiment of thepresent invention cycloheteroalkyl is selected from: morpholine,pyrrolidine, piperazine, and piperidine. In another embodiment of thepresent invention, cycloheteroalkyl is pyrrolidine.

In another embodiment, C₂₋₁₀cycloheteroalkyl is a non-aromaticmonocyclic, bicyclic, spiro or bridged carbocyclic ring having from 2 to10 carbon atoms, and containing 1 or 2 heteroatoms selected from O. Inanother embodiment of the present invention, cycloheteroalkyl isdianhydro-mannitol. In another embodiment of the present invention,cycloheteroalkyl is 1, 4:3, 6-dianhydro-mannitol. In another embodimentof the present invention, cycloheteroalkyl is 1, 4:3,6-dianhydro-D-mannitol. In another embodiment of the present invention,cycloheteroalkyl is hexahydrofuro[3,2-b]furan. In a class of thisembodiment, cycloheteroalkyl is 2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan.

In another embodiment, C₂₋₁₀cycloheteroalkyl is pyrrolidine. In anotherembodiment, C₂₋₇cycloheteroalkyl is piperidine. In another embodiment,C₂₋₆cycloheteroalkyl is morpholine or pyrrolidine.

“Cycloheteroalkenyl” means aromatic monocyclic, bicyclic, spiro orbridged rings each having from 2 to 14 carbon atoms containing at leastone double bond and containing 1, 2, 3, 4 or 5 heteroatoms selected fromN, NH, O and S. Examples of cycloheteroalkenyl include1,2,4-oxadiazol-5-one, 1,2,4-thiadiazol-5-one, 1,2,4-triazol-3-one, and1,2,3,6-tetrahydropyridine, dihydro-1,3,4-oxadiazole, and[1,6]-dihydropyridine and the like. In one embodiment of the presentinvention, cycloheteroalkenyl is dihydro-1,3,4-oxadiazole. In anotherembodiment of the present invention, cycloheteroalkenyl is[1,6]-dihydropyridine.

In another embodiment, C₂₋₁₀cycloheteroalkenyl is a non-aromatic,bicyclic carbocyclic ring having from 2 to 10 carbon atoms, andcontaining 1, 2 or 3 heteroatoms selected from N, and NH. In a class ofthis embodiment, cycloheteroalkenyl is dihydropyrrolo[3,4-c]pyrazole. Inanother class of this embodiment, cycloheteroalkenyl is4,6-dihydropyrrolo[3,4-c]pyrazole.

In another embodiment, C₂₋₆cycloheteroalkenyl is a non-aromatic,bicyclic carbocyclic ring having from 2 to 6 carbon atoms, andcontaining 1 or 2 heteroatoms selected from N, and NH. In a class ofthis embodiment, cycloheteroalkenyl is dihydroimidazole ortetrahydropyrimidine. In another class of this embodiment,cycloheteroalkenyl is 2,5 dihydro-1H-imidazole or1,4,5,6-tetrahydropyrimidine. In another class of this embodiment,cycloheteroalkenyl is dihydroimidazole. In another class of thisembodiment, cycloheteroalkenyl is 2,5 dihydro-1H-imidazole. In anotherclass of this embodiment, cycloheteroalkenyl is tetrahydropyrimidine. Inanother class of this embodiment, cycloheteroalkenyl is1,4,5,6-tetrahydropyrimidine.

“Aryl” means a monocyclic, bicyclic or tricyclic ring system containing5-14 carbon atoms, wherein at least one of the rings is aromatic. Arylthus includes ring systems in which an aromatic ring is fused to anon-aromatic ring, such as a cycloalkyl or cycloalkenyl ring. Examplesof aryl include phenyl, naphthalene, biphenyl, indane and5,6,7,8-tetrahydronaphthalene, and the like. In one embodiment of thepresent invention, aryl is phenyl, naphthalene, biphenyl, indane, and5,6,7,8-tetrahydronaphthalene. In another embodiment of the presentinvention, aryl is phenyl, naphthalene, indane and5,6,7,8-tetrahydronaphthalene. In one class of this embodiment, aryl isphenyl or naphthalene. In another class of this embodiment, aryl isphenyl. In another class of this embodiment, aryl is naphthalene.

“Heteroaryl” means a monocyclic, bicyclic or tricyclic ring systemcontaining 5-14 carbon atoms and containing 1, 2, 3, 4 or 5 heteroatomsselected from N, NH, O and S wherein at least one of the heteroatomcontaining rings is aromatic. Heteroaryl thus includes ring systems inwhich an aromatic heteroatom containing ring is fused to a non-aromaticring, such as a cycloalkyl, cycloalkenyl, cycloheteroalkyl orcycloheteroalkenyl ring, and also includes ring systems in which an arylring is fused to a non-aromatic heteroatom containing ring, such asacycloheteroalkyl or cycloheteroalkenyl ring. Examples of heteroarylsinclude: pyrazole, pyridine, pyrazine, pyrimidine, thiazole, thiophene,benzoimidazole, quinoline, isoquinoline, indole, indazole, carbazole,benzotriazole, benzofuran, benzothiazole, benzothiophene,benzoisooxazole, oxazole, furan, benzoxazole, isoxazole, indoline,isoindoline, tetrazole, imidazole, oxadiazole, thiadiazole, triazole,benzothiazole, benzopyrazole, imidazopyridine, benzodioxole,dihydropyridine, dihydropyrrolopyridine, dihydrobenzooxazine,benzodioxole, benzodioxine, pyrrolopyridine, triazolopyridine,dihydropyridooxazine, dihydrobenzoxazine, dihydroindole,dihydroisoindole, dihydrobenzoimidazole, dihydroquinoline,tetrahydroisoquinoline, tetrahydrocyclopentaindole,tetrahydroquinoxaline, and tetrahydropyridine. In one embodiment of thepresent invention, heteroaryl is selected from: imidazole, pyrazole,pyridine, pyrazine, pyrimidine, thiazole, thiophene, benzoimidazole,quinoline, isoquinoline, indole, indazole, carbazole, benzotriazole,benzofuran, benzothiazole, benzo[b]thiophene, benzo[d]isooxazole,3,4-dihydro-2H-benzo[1,4]oxazine, benzo[1,3]dioxole, benzo[1,4]dioxine,1H-pyrrolo[2,3-b]pyridine, 1,6-dihydro-pyridine,[1,2,4]triazolo[4,3-a]pyridine, 3,4 dihydropyrido[3,2-b][1,4]oxazine,3,4-dihydro-2H-1,4-benzoxazine, 2,3-dihydro-1H-indole,2,3-dihydro-1H-isoindole, 2,3-dihydrobenzoimidazole,1,2-dihydroquinoline, 1,2,3,4-tetrahydroisoquinoline,1,2,3,4-tetrahydrocyclopenta[b]indole, 1,2,3,4-tetrahydroquinoxaline,and 1,2,3,6-tetrahydropyridine. In another embodiment of the presentinvention, heteroaryl is tetrazole. In another embodiment, heteroaryl isselected from: pyrazole, pyridine, pyrimidine, isoxazole, imidazole,oxazole, triazole, tetrazole, oxadiazole, thiazole, thiadiazole, andbenzoxazole. In another embodiment of this invention, heteroaryl istetrazole. In another embodiment, heteroaryl is pyridine, pyrimidine,oxadiazole, oxazole, tetrazole, pyrazole, thiazole, triazole, orpyridazine.

In another embodiment of the present invention, dihydropyrrolopyrazoleis 4,6-dihydropyrrolo[3,4-c]pyrazole,

In another embodiment of the present invention, dihydroimidazole is4,5-dihydro-1H-imidazole.

“Halogen” includes fluorine, chlorine, bromine and iodine. In oneembodiment of the present invention, halogen is selected from fluorine,chlorine, and bromine. In another embodiment of the present invention,halogen is selected from fluorine, and chlorine. In another embodimentof the present invention, halogen is fluorine. In another embodiment ofthe present invention, halogen is chlorine.

When any variable (e.g., R¹, R^(a), etc.) occurs more than one time inany constituent or in formula I, its definition on each occurrence isindependent of its definition at every other occurrence. Also,combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds. A squiggly line across abond in a substituent variable represents the point of attachment.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.For example, a C₁₋₅alkylcarbonylamino C₁₋₆alkyl substituent isequivalent to:

In choosing compounds of the present invention, one of ordinary skill inthe art will recognize that the various substituents, i.e. R¹, R², etc.,are to be chosen in conformity with well-known principles of chemicalstructure connectivity and stability.

The term “substituted” shall be deemed to include multiple degrees ofsubstitution by a named substitutent. Where multiple substituentmoieties are disclosed or claimed, the substituted compound can beindependently substituted by one or more of the disclosed or claimedsubstituent moieties, singly or plurally. By independently substituted,it is meant that the (two or more) substituents can be the same ordifferent.

Compounds of Formula I may contain one or more asymmetric centers andcan thus occur as racemates and racemic mixtures, single enantiomers,diastereomeric mixtures and individual diastereomers. The presentinvention is meant to comprehend all such isomeric forms of thecompounds of Formula I.

Some of the compounds described herein contain olefinic double bonds,and unless specified otherwise, are meant to include both E and Zgeometric isomers.

Tautomers are defined as compounds that undergo rapid proton shifts fromone atom of the compound to another atom of the compound. Some of thecompounds described herein may exist as tautomers with different pointsof attachment of hydrogen. Such an example may be a ketone and its enolform known as keto-enol tautomers. The individual tautomers as well asmixture thereof are encompassed with compounds of Formula I.

Examples of tautomers include, but are not limited to:

In the compounds of general formula I, the atoms may exhibit theirnatural isotopic abundances, or one or more of the atoms may beartificially enriched in a particular isotope having the same atomicnumber, but an atomic mass or mass number different from the atomic massor mass number predominately found in nature. The present invention ismeant to include all suitable isotopic variations of the compounds ofstructural formula I. For example, different isotopic forms of hydrogen(H) include protium (¹H) and deuterium (²H). Protium is the predominanthydrogen isotope found in nature. Enriching for deuterium may affordcertain therapeutic advantages, such as increasing in vivo half-life orreducing dosage requirements, or may provide a compound useful as astandard for characterization of biological samples.Isotopically-enriched compounds within structural formula I, can beprepared without undue experimentation by conventional techniques wellknown to those skilled in the art or by processes analogous to thosedescribed in the Schemes and Examples herein using appropriateisotopically-enriched reagents and/or intermediates.

Compounds of the Formula I may be separated into diastereoisomeric pairsof enantiomers by, for example, fractional crystallization from asuitable solvent, for example MeOH or ethyl acetate or a mixturethereof. The pair of enantiomers thus obtained may be separated intoindividual stereoisomers by conventional means, for example by the useof an optically active amine as a resolving agent or on a chiral HPLCcolumn.

Alternatively, any enantiomer of a compound of the general Formula I maybe obtained by stereospecific synthesis using optically pure startingmaterials or reagents of known configuration.

Furthermore, some of the crystalline forms for compounds of the presentinvention may exist as polymorphs and as such are intended to beincluded in the present invention. In addition, some of the compounds ofthe instant invention may form solvates with water or common organicsolvents. Such solvates are encompassed within the scope of thisinvention.

It is generally preferable to administer compounds of the presentinvention as enantiomerically pure formulations. Racemic mixtures can beseparated into their individual enantiomers by any of a number ofconventional methods. These include chiral chromatography,derivatization with a chiral auxiliary followed by separation bychromatography or crystallization, and fractional crystallization ofdiastereomeric salts.

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc, and the like. Particularly preferred are theammonium, calcium, magnesium, potassium, and sodium salts. Salts derivedfrom pharmaceutically acceptable organic non-toxic bases include saltsof primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, and basic ionexchange resins, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine,histidine, hydrabamine, isopropylamine, lysine, methylglucamine,morpholine, piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, and the like. The term “pharmaceutically acceptable salt”further includes all acceptable salts such as acetate, trifluoroacetate,lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate,maleate, bisulfate, mandelate, bitartrate, mesylate, borate,methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate,camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate,N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate,edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate,esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate,polygalacturonate, gluconate, salicylate, glutamate, stearate,glycollylarsanilate, sulfate, hexylresorcinate, subacetate, hydrabamine,succinate, hydrobromide, tannate, hydrochloride, tartrate,hydroxynaphthoate, teoclate, iodide, tosylate, isothionate,triethiodide, lactate, panoate, valerate, and the like which can be usedas a dosage form for modifying the solubility or hydrolysischaracteristics or can be used in sustained release or pro-drugformulations.

It will be understood that, as used herein, references to the compoundsof Formula I are meant to also include the pharmaceutically acceptablesalts.

Compounds of the present invention are activators of the AMP-activatedprotein kinase. The methods of treatment of this invention comprise amethod of activating AMPK-activated protein kinase and treatingAMPK-activated protein kinase mediated diseases by administering to apatient in need of such treatment a non-toxic therapeutically effectiveamount of a compound of this invention that activate AMPK-activatedprotein kinase.

AMP-activated protein kinase (AMPK) is a heterotrimeric enzyme composedof a catalytic α subunit and regulatory β and γ subunits. There are twogenes encoding isoforms of both the α and β subunits (α1, α2, β1 and β2)and three genes encoding isoforms of the γ subunit (γ1, γ2 and γ3)leading to 12 possible heterotrimeric combinations. The α2 isoform ispredominately found in skeletal and cardiac muscle AMPK; both the α1 andα2 isoforms are found in hepatic AMPK; while in pancreatic islet β-cellsthe α1 isoform AMPK predominates. In particular, the compounds ofstructural formula I are activators of at least one heterotrimericisoform of AMP-activated protein kinase.

An “activator” is a compound that either increases the activity(phosphorylation of downstream substrates) of fully phosphorylated AMPKor that increases the phosphorylation of AMPK.

The compounds of the present invention are efficacious in the treatmentand prevention of diseases, disorders and conditions that are responsiveto the activation of AMP-activated protein kinase. As AMPK activators,the compounds of the present invention may be useful for the treatmentof Type 2 diabetes, insulin resistance, hyperglycemia, obesity,hyperinsulinemia, glucose intolerance, atherosclerosis, MetabolicSyndrome, hypertension, high hepatic glucose output, high blood glucoseconcentrations, nonalcoholic steatohepatitis, protection againstischemia and reperfusion damage, and lipid disorders, such asdyslipidemia, elevated levels of plasma triglycerides, elevated levelsof free fatty acids, elevated levels of cholesterol, high levels of lowdensity lipoprotein (LDL) and low levels of high density lipoprotein(HDL). The compounds of the present invention may also be useful for thetreatment of cancer, hypoxia and glucocorticoid-induced apoptosis. Thecompounds of the present invention may also be useful for the treatmentof sarcopenia by treating or preventing the loss of skeletal musclemass, including but not limited to a loss of skeletal muscle mass due toaging.

One or more of the following diseases may be treated by theadministration of a therapeutically effective amount of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, to a patientin need of treatment or prevention of: (1) non-insulin dependentdiabetes mellitus (Type 2 diabetes); (2) hyperglycemia; (3) MetabolicSyndrome; (4) obesity; (5) hypercholesterolemia; (6)hypertriglyceridemia (elevated levels oftriglyceride-rich-lipoproteins); (7) mixed or diabetic dyslipidemia; (8)low HDL cholesterol; (9) high LDL cholesterol; (10) atherosclerosis;(11) atherosclerosis, (12) hypertension, and (13) sarcopenia.

In one embodiment of the present invention, the compounds of Formula Imay be useful for the treatment of one or more of the following diseasesby administering a therapeutically effective amount to a patient in needof treatment: (1) Type 2 diabetes; (2) hyperglycemia; (3) MetabolicSyndrome; (4) obesity; (5) hypercholesterolemia; and (6) hypertension.

The compounds of structural Formula I may also be used for manufacturinga medicament for use in the treatment of one or more of the abovediseases.

The compounds may also be effective in lowering glucose and lipids indiabetic patients and in non-diabetic patients who have impaired glucosetolerance and/or are in a pre-diabetic condition. The compounds mayameliorate hyperinsulinemia, which often occurs in diabetic orpre-diabetic patients, by modulating the swings in the level of serumglucose that often occurs in these patients. The compounds may also beeffective in treating or reducing insulin resistance. The compounds maybe effective in treating or preventing gestational diabetes.

The compounds, compositions, methods and medicaments as described hereinmay also be effective in: a) reducing the risks of adverse sequelaeassociated with metabolic syndrome, b) reducing the risk of developingatherosclerosis, c) delaying the onset of atherosclerosis, and/or d)reducing the risk of sequelae of atherosclerosis. Sequelae ofatherosclerosis include angina, claudication, heart attack, stroke, andothers. By keeping hyperglycemia under control, the compounds may alsobe effective in delaying or preventing vascular restenosis and diabeticretinopathy.

The compounds of this invention may also have utility in improving orrestoring β-cell function, and may be useful in treating type 1diabetes, and in delaying or preventing a patient with Type 2 diabetesfrom needing insulin therapy.

Other possible outcomes of treatment with the compounds of the presentinvention may be: 1) a decrease in fatty acid synthesis; 2) an increasein fatty acid oxidation and ketogenesis; 3) a decrease in cholesterolsynthesis, lipogenesis, and triglyceride synthesis; 4) a decrease inblood glucose levels and concentration; 5) an improvement in glucosehomeostasis; 6) a normalization of glucose metabolism; 7) a decrease inblood pressure; 8) an increase in HDL; 9) a decrease in LDL; 10) adecrease in plasma triglycerides; 11) a decrease in free fatty acids;12) a decrease in hepatic glucose output; 13) an improvement in insulinaction; 14) a decrease in blood pressure; 15) an improvement in insulinsensitivity; 16) a suppression of hepatic glucose output; 17) aninhibition of de novo lipogenesis; 18) stimulation of muscle glucoseuptake; 19) modulation of insulin secretion by pancreatic β cells; 20) adecrease in body weight; 21) an increase in skeletal muscle mass; and22) a prevention in the loss of skeletal muscle mass.

The compounds of the present invention may be efficacious in treatingone or more of the following diseases: (1) Type 2 diabetes (also knownas non-insulin dependent diabetes mellitus, or NIDDM), (2)hyperglycemia, (3) impaired glucose tolerance, (4) insulin resistance,(5) obesity, (6) lipid disorders, (7) dyslipidemia, (8) hyperlipidemia,(9) hypertriglyceridemia, (10) hypercholesterolemia, (11) low HDLlevels, (12) high LDL levels, (13) atherosclerosis and its sequelae,(14) vascular restenosis, (15) abdominal obesity, (16) retinopathy, (17)metabolic syndrome, (18) high blood pressure (hypertension), and (19)insulin resistance.

One aspect of the invention provides potential methods for the treatmentand control of mixed or diabetic dyslipidemia, hypercholesterolemia,atherosclerosis, low HDL levels, high LDL levels, hyperlipidemia, and/orhypertriglyceridemia, which comprises administering to a patient in needof such treatment a therapeutically effective amount of a compound offormula I alone or with a cholesterol biosynthesis inhibitor,particularly an HMG-CoA reductase inhibitor such as lovastatin,simvastatin, rosuvastatin, pravastatin, fluvastatin, atorvastatin,rivastatin, itavastatin, or ZD-4522. The compound of formula I may alsobe used advantageously in combination with other lipid lowering drugssuch as cholesterol absorption inhibitors (for example stanol esters,sterol glycosides such as tiqueside, and azetidinones such asezetimibe), ACAT inhibitors (such as avasimibe), CETP inhibitors (forexample anacetrapib, torcetrapib, and those described in publishedapplications WO2005/100298, WO2006/014413, and WO2006/014357), niacinand niacin receptor agonists, bile acid sequestrants, microsomaltriglyceride transport inhibitors, and bile acid reuptake inhibitors.These combination treatments may be effective for the treatment orcontrol of one or more related conditions selected from the groupconsisting of hypercholesterolemia, atherosclerosis, hyperlipidemia,hypertriglyceridemia, dyslipidemia, high LDL, and low HDL.

The present invention also provides potential methods and medicamentsfor the treatment, control, or prevention of Type 2 diabetes byadministering the compounds and pharmaceutical compositions of thepresent invention alone or in combination with a therapeuticallyeffective amount of another agent known to be useful to treat thecondition. The present invention also relates to potential methods andmedicaments for the treatment, control, or prevention of diabetesrelated disorders by administering the compounds and pharmaceuticalcompositions of the present invention alone, or in combination. Thepresent invention also relates to potential methods and medicaments forthe treatment and prevention of diabetes in pre-diabetic subject byadministering the compounds and pharmaceutical compositions of thepresent invention alone, or in combination.

The present invention also relates to potential methods and medicamentsfor the treatment, control, or prevention of obesity by administeringthe compounds and pharmaceutical compositions of the present invention,alone or in combination with a therapeutically effective amount ofanother agent known to be useful to treat the condition. The presentinvention also relates to potential methods and medicaments for thetreatment, control, or prevention of obesity related disorders byadministering the compounds and pharmaceutical compositions of thepresent invention alone, or in combination. The present invention alsorelates to potential methods and medicaments for the treatment andprevention of obesity in overweight subject by administering thecompounds and pharmaceutical compositions of the present inventionalone, or in combination. The compounds may also be useful for thetreatment of obesity related disorders.

The present invention also relates to potential methods and medicamentsfor the treatment, control, or prevention of hyperglycemia byadministering the compounds and pharmaceutical compositions of thepresent invention, alone or in combination with a therapeuticallyeffective amount of another agent known to be useful to treat thecondition.

The present invention also relates to potential methods and medicamentsfor the treatment, control, or prevention of insulin resistance byadministering the compounds and pharmaceutical compositions of thepresent invention, alone or in combination with a therapeuticallyeffective amount of another agent known to be useful to treat thecondition.

The present invention also relates to potential methods and medicamentsfor the treatment, control, or prevention of lipid disorders byadministering the compounds and pharmaceutical compositions of thepresent invention, alone or in combination with a therapeuticallyeffective amount of another agent known to be useful to treat thecondition. The present invention also relates to potential methods andmedicaments for the treatment, control, or prevention of dyslipidemiarelated disorders and lipid disorder-related disorders by administeringthe compounds and pharmaceutical compositions of the present inventionalone, or in combination.

The present invention also relates to potential methods and medicamentsfor the treatment, control, or prevention of atherosclerosis byadministering the compounds and pharmaceutical compositions of thepresent invention, alone or in combination with a therapeuticallyeffective amount of another agent known to be useful to treat thecondition.

The present invention also relates to potential methods and medicamentsfor the treatment, control, or prevention of hypertension byadministering the compounds and pharmaceutical compositions of thepresent invention, alone or in combination with a therapeuticallyeffective amount of another agent known to be useful to treat thecondition. The present invention also relates to potential methods andmedicaments for the treatment and prevention of hypertension inpre-hypertensive subject by administering the compounds andpharmaceutical compositions of the present invention alone, or incombination.

The present invention also relates to potential methods and medicamentsfor the treatment, control, or prevention of Metabolic Syndrome byadministering the compounds and pharmaceutical compositions of thepresent invention, alone or in combination with a therapeuticallyeffective amount of another agent known to be useful to treat thecondition.

The compounds of the present invention wherein Y is a tetrahydropyranderivative have the unexpected benefit of reduced inhibition ofrecombinant CYP2C9 or CYP2C8 isozymes, compared to analogous compoundswherein Y is phenyl. In particular, the compounds of the presentinvention wherein Y is a tetrahydropyran derivative have the unexpectedbenefit of reduced inhibition of recombinant CYP2C9 or CYP2C8 isozymes,compared to analogous compounds wherein Y is benzoic acid.

Inhibition of a recombinant CYP isozyme is measured by using a probesubstrate, which upon oxidation by human liver microsome, is convertedto a metabolite which is monitored by LC-MS/MS. NADPH or NADPHregenerating system are used as electron donors for the microsomecatalytic cycle. Control incubations containing no inhibitors performedto evaluate the 100% activities. The activity of the enzyme is evaluatedin the presence of various concentrations of test compounds. Standardspecific enzyme inhibitors are used as positive controls. Inhibitioncurves are generated and IC50 values are calculated for testedcompounds.

Co-administration of CYP inhibitors with pharmaceutical agents that aremetabolized by the enzyme can result in elevated circulatingconcentrations of the pharmaceutical agents. This can lead to adverseevents.

The term “diabetes,” as used herein, includes both insulin-dependentdiabetes mellitus (i.e., IDDM, also known as type 1 diabetes) andnon-insulin-dependent diabetes mellitus (i.e., NIDDM, also known as Type2 diabetes). Type 1 diabetes, or insulin-dependent diabetes, is theresult of an absolute deficiency of insulin, the hormone which regulatesglucose utilization. Type 2 diabetes, or insulin-independent diabetes(i.e., non-insulin-dependent diabetes mellitus), often occurs in theface of normal, or even elevated levels of insulin and appears to be theresult of the inability of tissues to respond appropriately to insulin.Most of the Type 2 diabetics are also obese. The compositions of thepresent invention may be useful for treating both Type 1 and Type 2diabetes. The term “diabetes associated with obesity” refers to diabetescaused by obesity or resulting from obesity. The compositions may beespecially effective for treating Type 2 diabetes. The compositions ofthe present invention may also be useful for treating and/or preventinggestational diabetes mellitus.

Diabetes is characterized by a fasting plasma glucose level of greaterthan or equal to 126 mg/dl. A diabetic subject has a fasting plasmaglucose level of greater than or equal to 126 mg/dl. A pre diabeticsubject is someone suffering from prediabetes. Prediabetes ischaracterized by an impaired fasting plasma glucose (FPG) level ofgreater than or equal to 110 mg/dl and less than 126 mg/dl; or impairedglucose tolerance; or insulin resistance. A prediabetic subject is asubject with impaired fasting glucose (a fasting plasma glucose (FPG)level of greater than or equal to 110 mg/dl and less than 126 mg/dl); orimpaired glucose tolerance (a 2 hour plasma glucose level of ≧140 mg/dland <200 mg/dl); or insulin resistance, resulting in an increased riskof developing diabetes.

Treatment of diabetes mellitus refers to the administration of acompound or combination of the present invention to treat a diabeticsubject. One outcome of treatment may be decreasing the glucose level ina subject with elevated glucose levels. Another outcome of treatment maybe decreasing insulin levels in a subject with elevated insulin levels.Another outcome of treatment may be decreasing plasma triglycerides in asubject with elevated plasma triglycerides. Another outcome of treatmentis decreasing LDL cholesterol in a subject with high LDL cholesterollevels. Another outcome of treatment may be increasing HDL cholesterolin a subject with low HDL cholesterol levels. Another outcome oftreatment is increasing insulin sensivity. Another outcome of treatmentmay be enhancing glucose tolerance in a subject with glucoseintolerance. Yet another outcome of treatment may be decreasing insulinresistance in a subject with increased insulin resistance or elevatedlevels of insulin. Prevention of diabetes mellitus, in particulardiabetes associated with obesity, refers to the administration of acompound or combination of the present invention to prevent the onset ofdiabetes in a subject in need thereof. A subject in need of preventingdiabetes is a prediabetic subject that is overweight or obese.

The term “diabetes related disorders” should be understood to meandisorders that are associated with, caused by, or result from diabetes.Examples of diabetes related disorders include retinal damage, kidneydisease, and nerve damage.

The term “atherosclerosis” as used herein encompasses vascular diseasesand conditions that are recognized and understood by physicianspracticing in the relevant fields of medicine. Atheroscleroticcardiovascular disease, coronary heart disease (also known as coronaryartery disease or ischemic heart disease), cerebrovascular disease andperipheral vessel disease are all clinical manifestations ofatherosclerosis and are therefore encompassed by the terms“atherosclerosis” and “atherosclerotic disease.” The combinationcomprised of a therapeutically effective amount of an anti-obesity agentin combination with a therapeutically effective amount of ananti-hypertensive agent may be administered to prevent or reduce therisk of occurrence, or recurrence where the potential exists, of acoronary heart disease event, a cerebrovascular event, or intermittentclaudication. Coronary heart disease events are intended to include CHDdeath, myocardial infarction (i.e., a heart attack), and coronaryrevascularization procedures. Cerebrovascular events are intended toinclude ischemic or hemorrhagic stroke (also known as cerebrovascularaccidents) and transient ischemic attacks. Intermittent claudication isa clinical manifestation of peripheral vessel disease. The term“atherosclerotic disease event” as used herein is intended to encompasscoronary heart disease events, cerebrovascular events, and intermittentclaudication. It is intended that persons who have previouslyexperienced one or more non-fatal atherosclerotic disease events arethose for whom the potential for recurrence of such an event exists. Theterm “atherosclerosis related disorders” should be understood to meandisorders associated with, caused by, or resulting from atherosclerosis.

The term “hypertension” as used herein includes essential, or primary,hypertension wherein the cause is not known or where hypertension is dueto greater than one cause, such as changes in both the heart and bloodvessels; and secondary hypertension wherein the cause is known. Causesof secondary hypertension include, but are not limited to obesity;kidney disease; hormonal disorders; use of certain drugs, such as oralcontraceptives, corticosteroids, cyclosporin, and the like. The term“hypertension” encompasses high blood pressure, in which both thesystolic and diastolic pressure levels are elevated (≧140 mmHg/≧90mmHg), and isolated systolic hypertension, in which only the systolicpressure is elevated to greater than or equal to 140 mm Hg, while thediastolic pressure is less than 90 mm Hg. Normal blood pressure may bedefined as less than 120 mmHg systolic and less than 80 mmHg diastolic.A hypertensive subject is a subject with hypertension. Apre-hypertensive subject is a subject with a blood pressure that isbetween 120 mmHg over 80 mmHg and 139 mmHg over 89 mmHg One outcome oftreatment is decreasing blood pressure in a subject with high bloodpressure. Treatment of hypertension refers to the administration of thecompounds and combinations of the present invention to treathypertension in a hypertensive subject. Treatment ofhypertension-related disorder refers to the administration of a compoundor combination of the present invention to treat thehypertension-related disorder. Prevention of hypertension, or ahypertension related disorder, refers to the administration of thecombinations of the present invention to a pre-hypertensive subject toprevent the onset of hypertension or a hypertension related disorder.The hypertension-related disorders herein are associated with, causedby, or result from hypertension. Examples of hypertension-relateddisorders include, but are not limited to: heart disease, heart failure,heart attack, kidney failure, and stroke.

Dyslipidemias and lipid disorders are disorders of lipid metabolismincluding various conditions characterized by abnormal concentrations ofone or more lipids (i.e. cholesterol and triglycerides), and/orapolipoproteins (i.e., apolipoproteins A, B, C and E), and/orlipoproteins (i.e., the macromolecular complexes formed by the lipid andthe apolipoprotein that allow lipids to circulate in blood, such as LDL,VLDL and IDL). Hyperlipidemia is associated with abnormally high levelsof lipids, LDL and VLDL cholesterol, and/or triglycerides. Treatment ofdyslipidemia refers to the administration of the combinations of thepresent invention to a dyslipidemic subject. Prevention of dyslipidemiarefers to the administration of the combinations of the presentinvention to a pre-dyslipidemic subject. A pre-dyslipidemic subject is asubject with higher than normal lipid levels, that is not yetdyslipidemic.

The terms “dyslipidemia related disorders” and “lipid disorder relateddisorders” should be understood to mean disorders associated with,caused by, or resulting from dyslipidemia or lipid disorders. Examplesof dylipidemia related disorder and lipid disorder related disordersinclude, but are not limited to: hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, low high density lipoprotein (HDL) levels, highplasma low density lipoprotein (LDL) levels, atherosclerosis and itssequelae, coronary artery or carotid artery disease, heart attack, andstroke.

The term “obesity” as used herein is a condition in which there is anexcess of body fat. The operational definition of obesity is based onthe Body Mass Index (BMI), which is calculated as body weight per heightin meters squared (kg/m²). “Obesity” refers to a condition whereby anotherwise healthy subject has a Body Mass Index (BMI) greater than orequal to 30 kg/m², or a condition whereby a subject with at least oneco-morbidity has a BMI greater than or equal to 27 kg/m². An “obesesubject” is an otherwise healthy subject with a Body Mass Index (BMI)greater than or equal to 30 kg/m² or a subject with at least oneco-morbidity with a BMI greater than or equal to 27 kg/m². An overweightsubject is a subject at risk of obesity. A “subject at risk of obesity”is an otherwise healthy subject with a BMI of 25 kg/m² to less than 30kg/m² or a subject with at least one co-morbidity with a BMI of 25 kg/m²to less than 27 kg/m².

The increased risks associated with obesity occur at a lower Body MassIndex (BMI) in Asians. In Asian countries, including Japan, “obesity”refers to a condition whereby a subject with at least oneobesity-induced or obesity-related co-morbidity, that requires weightreduction or that would be improved by weight reduction, has a BMIgreater than or equal to 25 kg/m². In Asian countries, including Japan,an “obese subject” refers to a subject with at least one obesity-inducedor obesity-related co-morbidity that requires weight reduction or thatwould be improved by weight reduction, with a BMI greater than or equalto 25 kg/m². In Asia-Pacific, a “subject at risk of obesity” is asubject with a BMI of greater than 23 kg/m² to less than 25 kg/m².

As used herein, the term “obesity” is meant to encompass all of theabove definitions of obesity.

Obesity-induced or obesity-related co-morbidities include, but are notlimited to, diabetes mellitus, non-insulin dependent diabetesmellitus—type 2, diabetes associated with obesity, impaired glucosetolerance, impaired fasting glucose, insulin resistance syndrome,dyslipidemia, hypertension, hypertension associated with obesity,hyperuricacidemia, gout, coronary artery disease, myocardial infarction,angina pectoris, sleep apnea syndrome, Pickwickian syndrome, fattyliver; cerebral infarction, cerebral thrombosis, transient ischemicattack, orthopedic disorders, arthritis deformans, lumbodynia,emmeniopathy, and infertility. In particular, co-morbidities include:hypertension, hyperlipidemia, dyslipidemia, glucose intolerance,cardiovascular disease, sleep apnea, and other obesity-relatedconditions.

Treatment of obesity and obesity-related disorders refers to theadministration of the compounds of the present invention to reduce ormaintain the body weight of an obese subject. One outcome of treatmentmay be reducing the body weight of an obese subject relative to thatsubject's body weight immediately before the administration of thecompounds of the present invention. Another outcome of treatment may bepreventing body weight regain of body weight previously lost as a resultof diet, exercise, or pharmacotherapy. Another outcome of treatment maybe decreasing the occurrence of and/or the severity of obesity-relateddiseases. The treatment may suitably result in a reduction in food orcalorie intake by the subject, including a reduction in total foodintake, or a reduction of intake of specific components of the diet suchas carbohydrates or fats; and/or the inhibition of nutrient absorption;and/or the inhibition of the reduction of metabolic rate; and in weightreduction in patients in need thereof. The treatment may also result inan alteration of metabolic rate, such as an increase in metabolic rate,rather than or in addition to an inhibition of the reduction ofmetabolic rate; and/or in minimization of the metabolic resistance thatnormally results from weight loss.

Prevention of obesity and obesity-related disorders refers to theadministration of the compounds of the present invention to reduce ormaintain the body weight of a subject at risk of obesity. One outcome ofprevention may be reducing the body weight of a subject at risk ofobesity relative to that subject's body weight immediately before theadministration of the compounds of the present invention. Anotheroutcome of prevention may be preventing body weight regain of bodyweight previously lost as a result of diet, exercise, orpharmacotherapy. Another outcome of prevention may be preventing obesityfrom occurring if the treatment is administered prior to the onset ofobesity in a subject at risk of obesity. Another outcome of preventionmay be decreasing the occurrence and/or severity of obesity-relateddisorders if the treatment is administered prior to the onset of obesityin a subject at risk of obesity. Moreover, if treatment is commenced inalready obese subjects, such treatment may prevent the occurrence,progression or severity of obesity-related disorders, such as, but notlimited to, arteriosclerosis, Type II diabetes, polycystic ovariandisease, cardiovascular diseases, osteoarthritis, dermatologicaldisorders, hypertension, insulin resistance, hypercholesterolemia,hypertriglyceridemia, and cholelithiasis.

The obesity-related disorders herein are associated with, caused by, orresult from obesity. Examples of obesity-related disorders includeovereating and bulimia, hypertension, diabetes, elevated plasma insulinconcentrations and insulin resistance, dyslipidemias, hyperlipidemia,endometrial, breast, prostate and colon cancer, osteoarthritis,obstructive sleep apnea, cholelithiasis, gallstones, heart disease,abnormal heart rhythms and arrythmias, myocardial infarction, congestiveheart failure, coronary heart disease, sudden death, stroke, polycysticovarian disease, craniopharyngioma, the Prader-Willi Syndrome,Frohlich's syndrome, GH-deficient subjects, normal variant shortstature, Turner's syndrome, and other pathological conditions showingreduced metabolic activity or a decrease in resting energy expenditureas a percentage of total fat-free mass, e.g, children with acutelymphoblastic leukemia. Further examples of obesity-related disordersare metabolic syndrome, also known as syndrome X, insulin resistancesyndrome, sexual and reproductive dysfunction, such as infertility,hypogonadism in males and hirsutism in females, gastrointestinalmotility disorders, such as obesity-related gastro-esophageal reflux,respiratory disorders, such as obesity-hypoventilation syndrome(Pickwickian syndrome), cardiovascular disorders, inflammation, such assystemic inflammation of the vasculature, arteriosclerosis,hypercholesterolemia, hyperuricaemia, lower back pain, gallbladderdisease, gout, and kidney cancer.

The compounds of formula I may also be useful for treating or preventingobesity and obesity-related disorders in cats and dogs. As such, theterm “mammal” includes companion animals such as cats and dogs.

The term “metabolic syndrome”, also known as syndrome X, is defined inthe Third Report of the National Cholesterol Education Program ExpertPanel on Detection, Evaluation and Treatment of High Blood Cholesterolin Adults (Adult Treatment Panel III, or ATP III), National Institutesof Health, 2001, NIH Publication No. 01-3670. E. S. Ford et al., JAMA,vol. 287 (3), Jan. 16, 2002, pp 356-359. Briefly, a person is defined ashaving metabolic syndrome if the person has three or more of thefollowing disorders: abdominal obesity, hypertriglyceridemia, low HDLcholesterol, high blood pressure, and high fasting plasma glucose. Thecriteria for these are defined in ATP-III. Treatment of metabolicsyndrome refers to the administration of the combinations of the presentinvention to a subject with metabolic syndrome. Prevention of metabolicsyndrome refers to the administration of the combinations of the presentinvention to a subject with two of the disorders that define metabolicsyndrome. A subject with two of the disorders that define metabolicsyndrome is a subject that has developed two of the disorders thatdefine metabolic syndrome, but has not yet developed three or more ofthe disorders that define metabolic syndrome.

The terms “administration of” and or “administering a” compound shouldbe understood to mean providing a compound of the invention or a prodrugof a compound of the invention to the individual or mammal in need oftreatment.

The administration of the compound of structural formula I in order topractice the present methods of therapy is carried out by administeringan effective amount of the compound of structural formula I to themammal in need of such treatment or prophylaxis. The need for aprophylactic administration according to the methods of the presentinvention is determined via the use of well known risk factors. Theeffective amount of an individual compound is determined, in the finalanalysis, by the physician or veterinarian in charge of the case, butdepends on factors such as the exact disease to be treated, the severityof the disease and other diseases or conditions from which the patientsuffers, the chosen route of administration other drugs and treatmentswhich the patient may concomitantly require, and other factors in thephysician's judgment.

The usefulness of the present compounds in these diseases or disordersmay be demonstrated in animal disease models that have been reported inthe literature.

The magnitude of prophylactic or therapeutic dose of a compound ofFormula I will, of course, vary with the nature of the severity of thecondition to be treated and with the particular compound of Formula Iand its route of administration. It will also vary according to the age,weight and response of the individual patient. In general, the dailydose range lie within the range of from about 0.001 mg to about 100 mgper kg body weight of a mammal, preferably 0.01 mg to about 50 mg perkg, and most preferably 0.1 to 10 mg per kg, in single or divided doses.On the other hand, it may be necessary to use dosages outside theselimits in some cases.

For use where a composition for intravenous administration is employed,a suitable dosage range is from about 0.001 mg to about 100 mg in oneembodiment from about 0.01 mg to about 50 mg, and in another embodimentfrom 0.1 mg to 10 mg of a compound of Formula I per kg of body weightper day.

In the case where an oral composition is employed, a suitable dosagerange is, e.g. from about 0.01 mg to about 1000 mg of a compound ofFormula I per day. In one embodiment, the range is from about 0.1 mg toabout 10 mg per day. For oral administration, the compositions arepreferably provided in the form of tablets containing from 0.01 to 1,000mg, preferably 0.01, 0.05, 0.1, 0.5, 1, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10,12, 12.5, 15, 20, 25, 30, 40, 50, 100, 250, 500, 750 or 1000 milligramsof the active ingredient for the symptomatic adjustment of the dosage tothe patient to be treated.

Another aspect of the present invention provides pharmaceuticalcompositions which comprises a compound of Formula I and apharmaceutically acceptable carrier. The term “composition”, as inpharmaceutical composition, is intended to encompass a productcomprising the active ingredient(s), and the inert ingredient(s)(pharmaceutically acceptable excipients) that make up the carrier, aswell as any product which results, directly or indirectly, fromcombination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical compositions of the presentinvention encompass any composition made by admixing a compound ofFormula I, additional active ingredient(s), and pharmaceuticallyacceptable excipients.

Any suitable route of administration may be employed for providing amammal, particularly a human or a companion animal such as a dog or cat,with an effective dosage of a compound of the present invention. Forexample, oral, rectal, topical, parenteral, ocular, pulmonary, and nasalroutes of administration, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like.

The pharmaceutical compositions of the present invention comprise acompound of Formula I as an active ingredient or a pharmaceuticallyacceptable salt thereof, and may also contain a pharmaceuticallyacceptable carrier and optionally other therapeutic ingredients. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof. Thecompositions include compositions suitable for oral, rectal, topical,parenteral (including subcutaneous, intramuscular, and intravenous),ocular (ophthalmic), pulmonary (aerosol inhalation), or nasaladministration, although the most suitable route in any given case willdepend on the nature and severity of the conditions being treated and onthe nature of the active ingredient. They may be conveniently presentedin unit dosage form and prepared by any of the methods well-known in theart of pharmacy.

For administration by inhalation, the compounds of the present inventionare conveniently delivered in the form of an aerosol spray presentationfrom pressurized packs or nebulizers, or as powders which may beformulated and the powder composition may be inhaled with the aid of aninsufflation powder inhaler device. The preferred delivery systems forinhalation are metered dose inhalation (MDI) aerosol, which may beformulated as a suspension or solution of a compound of Formula I insuitable propellants, such as fluorocarbons or hydrocarbons and drypowder inhalation (DPI) aerosol, which may be formulated as a dry powderof a compound of Formula I with or without additional excipients.

Suitable topical formulations of a compound of formula I includetransdermal devices, aerosols, creams, solutions, ointments, gels,lotions, dusting powders, and the like. The topical pharmaceuticalcompositions containing the compounds of the present inventionordinarily include about 0.005% to 5% by weight of the active compoundin admixture with a pharmaceutically acceptable vehicle. Transdermalskin patches useful for administering the compounds of the presentinvention include those known to those of ordinary skill in that art.

In practical use, the compounds of Formula I can be combined as theactive ingredient in intimate admixture with a pharmaceutical carrieraccording to conventional pharmaceutical compounding techniques. Thecarrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like in the case of oral liquidpreparations, such as, for example, suspensions, elixirs and solutions;or carriers such as starches, sugars, microcrystalline cellulose,diluents, granulating agents, lubricants, binders, disintegrating agentsand the like in the case of oral solid preparations such as, forexample, powders, capsules and tablets, with the solid oral preparationsbeing preferred over the liquid preparations. Because of their ease ofadministration, tablets and capsules represent the most advantageousoral dosage unit form in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be coated by standardaqueous or nonaqueous techniques.

In addition to the common dosage forms set out above, the compounds ofFormula I may also be administered by controlled release means and/ordelivery devices such as those described in U.S. Pat. Nos. 3,845,770;3,916,899; 3,536,809; 3,598,123; 3,630,200 and 4,008,719.

Pharmaceutical compositions of the present invention suitable for oraladministration may be presented as discrete units such as capsules(including timed release and sustained release formulations), pills,cachets, powders, granules or tablets each containing a predeterminedamount of the active ingredient, as a powder or granules or as asolution or a suspension in an aqueous liquid, a non-aqueous liquid, anoil-in-water emulsion or a water-in-oil liquid emulsion, includingelixirs, tinctures, solutions, suspensions, syrups and emulsions. Suchcompositions may be prepared by any of the methods of pharmacy but allmethods include the step of bringing into association the activeingredient with the carrier which constitutes one or more necessaryingredients. In general, the compositions are prepared by uniformly andintimately admixing the active ingredient with liquid carriers or finelydivided solid carriers or both, and then, if necessary, shaping theproduct into the desired presentation. For example, a tablet may beprepared by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared by compressingin a suitable machine, the active ingredient in a free-flowing form suchas powder or granules, optionally mixed with a binder, lubricant, inertdiluent, surface active or dispersing agent. Molded tablets may be madeby molding in a suitable machine, a mixture of the powdered compoundmoistened with an inert liquid diluent. Desirably, each tablet cachet orcapsule contains from about 0.01 to 1,000 mg, particularly 0.01, 0.05,0.1, 0.5, 1.0, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 25, 30, 40, 50,75, 100, 125, 150, 175, 180, 200, 225, 250, 500, 750 and 1,000milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the patient to be treated.

Additional suitable means of administration of the compounds of thepresent invention include injection, intravenous bolus or infusion,intraperitoneal, subcutaneous, intramuscular, intranasal, and topical,with or without occlusion.

Exemplifying the invention is a pharmaceutical composition comprisingany of the compounds described above and a pharmaceutically acceptablecarrier. Also exemplifying the invention is a pharmaceutical compositionmade by combining any of the compounds described above and apharmaceutically acceptable carrier. An illustration of the invention isa process for making a pharmaceutical composition comprising combiningany of the compounds described above and a pharmaceutically acceptablecarrier.

The dose may be administered in a single daily dose or the total dailydosage may be administered in divided doses of two, three or four timesdaily. Furthermore, based on the properties of the individual compoundselected for administration, the dose may be administered lessfrequently, e.g., weekly, twice weekly, monthly, etc. The unit dosagewill, of course, be correspondingly larger for the less frequentadministration.

When administered via intranasal routes, transdermal routes, by rectalor vaginal suppositories, or through a continual intravenous solution,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen.

The following are examples of representative pharmaceutical dosage formsfor the compounds of Formula I:

Injectable Suspension (I.M.) mg/mL Tablet mg/tablet Compound of 10Compound of Formula I 25 Formula I Methylcellulose 5.0 MicrocrystallineCellulose 415 Tween 80 0.5 Povidone 14.0 Benzyl alcohol 9.0Pregelatinized Starch 43.5 Benzalkonium chloride 1.0 Magnesium Stearate2.5 Water for injection to a total volume of 1 mL 500 mg/ Per Capsulecapsule Aerosol canister Compound of 25 Compound of Formula I  24 mgFormula I Lactose Powder 573.5 Lecithin, NF Liq. Conc.  1.2 mg MagnesiumStearate 1.5 Trichlorofluoromethane, NF 4.025 g 600Dichlorodifluoromethane, NF 12.15 g

Compounds of Formula I may be used in combination with other drugs thatare used in the treatment/prevention/suppression or amelioration of thediseases, disorders or conditions for which compounds of Formula I maybe useful. Such other drugs may be administered, by a route and in anamount commonly used therefor, contemporaneously or sequentially with acompound of Formula I. When a compound of Formula I is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofFormula I is preferred. Accordingly, the pharmaceutical compositions ofthe present invention include those that also contain one or more otheractive ingredients, in addition to a compound of Formula I. Examples ofother active ingredients that may be combined with a compound of FormulaI include, but are not limited to: other anti-diabetic agents,anti-dylipidemic agents, and anti-hypertensive agents, anti-obesityagents, and anorectic agents, which may be administered separately or inthe same pharmaceutical compositions.

The present invention also provides a method for the treatment orprevention of an AMPK-activated protein kinase (AMPK) mediated disease,which method comprises administration to a patient in need of suchtreatment or at risk of developing an AMPK mediated disease of an amountof an AMPK activator and an amount of one or more active ingredients,such that together they give effective relief.

In a further aspect of the present invention, there is provided apharmaceutical composition comprising an AMPK activator and one or moreactive ingredients, together with at least one pharmaceuticallyacceptable carrier or excipient.

Thus, according to a further aspect of the present invention there isprovided the use of an AMPK activator and one or more active ingredientsfor the manufacture of a medicament for the treatment or prevention ofan AMPK mediated disease. In a further or alternative aspect of thepresent invention, there is provided a product comprising an AMPKactivator and one or more active ingredients as a combined preparationfor simultaneous, separate or sequential use in the treatment orprevention of an AMPK mediated disease. Such a combined preparation maybe, for example, in the form of a twin pack.

It will be appreciated that for the potential treatment or prevention ofdiabetes, obesity, hypertension, Metabolic Syndrome, dyslipidemia,cancer, atherosclerosis, and related disorders thereof, a compound ofthe present invention may be used in conjunction with anotherpharmaceutical agent effective to treat that disorder.

The present invention also provides a potential method for the treatmentor prevention of diabetes, obesity, hypertension, Metabolic Syndrome,dyslipidemia, cancer, atherosclerosis, and related disorders thereof,which method comprises administration to a patient in need of suchtreatment an amount of a compound of the present invention and an amountof another pharmaceutical agent effective to threat that disorder, suchthat together they give effective relief.

The present invention also provides a potential method for the treatmentor prevention of diabetes, obesity, hypertension, Metabolic Syndrome,dyslipidemia, cancer, atherosclerosis, and related disorders thereof,which method comprises administration to a patient in need of suchtreatment an amount of a compound of the present invention and an amountof another pharmaceutical agent useful in treating that particularcondition, such that together they give effective relief.

Examples of other active ingredients that may be administered separatelyor in the same pharmaceutical composition in combination with a compoundof the formulas described herein include, but are not limited to:

(1) dipeptidyl peptidase-IV (DPP-4) inhibitors (e.g., sitagliptin,alogliptin, linagliptin, vildagliptin, saxagliptin, teneligliptin,omarigliptin);

(2) insulin sensitizers, including (i) PPARγ agonists, such as theglitazones (e.g. pioglitazone, AMG 131, MBX2044, mitoglitazone,lobeglitazone, IDR-105, rosiglitazone, and balaglitazone), and otherPPAR ligands, including (1) PPARα/γ dual agonists (e.g., ZYH2, ZYH1,GFT505, chiglitazar, muraglitazar, aleglitazar, sodelglitazar, andnaveglitazar); (2) PPARα agonists such as fenofibric acid derivatives(e.g., gemfibrozil, clofibrate, ciprofibrate, fenofibrate, bezafibrate),(3) selective PPARγ modulators (SPPARγM's), (e.g., such as thosedisclosed in WO 02/060388, WO 02/08188, WO 2004/019869, WO 2004/020409,WO 2004/020408, and WO 2004/066963); and (4) PPARγ partial agonists;(ii) biguanides, such as metformin and its pharmaceutically acceptablesalts, in particular, metformin hydrochloride, and extended-releaseformulations thereof, such as Glumetza™, Fortamet™, and GlucophageXR™;and (iii) protein tyrosine phosphatase-1B (PTP-1B) inhibitors (e.g.,ISIS-113715 and TTP814);

(3) insulin or insulin analogs (e.g., insulin detemir, insulinglulisine, insulin degludec, insulin glargine, insulin lispro, SBS1000and oral and inhalable formulations of insulin and insulin analogs);

(4) leptin and leptin derivatives and agonists;

(5) amylin and amylin analogs (e.g., pramlintide);

(6) sulfonylurea and non-sulfonylurea insulin secretagogues (e.g.,tolbutamide, glyburide, glipizide, glimepiride, mitiglinide,meglitinides, nateglinide and repaglinide);

(7) α-glucosidase inhibitors (e.g., acarbose, voglibose and miglitol);

(8) glucagon receptor antagonists (e.g., NOXG15, LY2409021);

(9) incretin mimetics, such as GLP-1, GLP-1 analogs, derivatives, andmimetics; and GLP-1 receptor agonists (e.g., dulaglutide, semaglutide,albiglutide, exenatide, liraglutide, lixisenatide, taspoglutide,GSK2374697, ADX72231, RG7685, NN9924, ZYOG1, CJC-1131, and BIM-51077,including intranasal, transdermal, and once-weekly formulationsthereof), and oxyntomodulin and oxyntomodulin analogs and derivatives;

(10) LDL cholesterol lowering agents such as (i) HMG-CoA reductaseinhibitors (e.g., simvastatin, lovastatin, pravastatin, crivastatin,fluvastatin, atorvastatin, pitavastatin and rosuvastatin), (ii) bileacid sequestering agents (e.g., colestilan, colestimide, colesevalamhydrochloride, colestipol, cholestyramine, and dialkylaminoalkylderivatives of a cross-linked dextran), (iii) inhibitors of cholesterolabsorption, (e.g., ezetimibe), and (iv) acyl CoA:cholesterolacyltransferase inhibitors, (e.g., avasimibe);

(11) HDL-raising drugs, (e.g., niacin and nicotinic acid receptoragonists, and extended-release versions thereof; MK-524A, which is acombination of niacin extended-release and the DP-1 antagonist MK-524);

(12) antiobesity compounds;

(13) agents intended for use in inflammatory conditions, such asaspirin, non-steroidal anti-inflammatory drugs or NSAIDs,glucocorticoids, and selective cyclooxygenase-2 or COX-2 inhibitors;

(14) antihypertensive agents, such as ACE inhibitors (e.g., lisinopril,enalapril, ramipril, captopril, quinapril, and tandolapril), A-IIreceptor blockers (e.g., losartan, candesartan, irbesartan, olmesartanmedoxomil, valsartan, telmisartan, and eprosartan), renin inhibitors(e.g., aliskiren), beta blockers, and calcium channel blockers;

(15) glucokinase activators (GKAs) (e.g., AZD6370);

(16) inhibitors of 11β-hydroxysteroid dehydrogenase type 1, (e.g., suchas those disclosed in U.S. Pat. No. 6,730,690, and LY-2523199);

(17) CETP inhibitors (e.g., anacetrapib, evacetrapib and torcetrapib);

(18) inhibitors of fructose 1,6-bisphosphatase, (e.g., such as thosedisclosed in U.S. Pat. Nos. 6,054,587; 6,110,903; 6,284,748; 6,399,782;and 6,489,476);

(19) inhibitors of acetyl CoA carboxylase-1 or 2 (ACC1 or ACC2);

(20) AMP-activated Protein Kinase (AMPK) activators, such as MB 1055,ETC 1002;

(21) other agonists of the G-protein-coupled receptors: (i) GPR-109,(ii) GPR-119 (e.g., MBX2982, APD597, GSK1292263, HM47000, and PSN821),and (iii) GPR-40 (e.g., TAK875, MR 1704, TUG 469, TUG499, ASP 4178);

(22) SSTR3 antagonists (e.g., such as those disclosed in WO2009/001836);

(23) neuromedin U receptor agonists (e.g., such as those disclosed in WO2009/042053, including, but not limited to, neuromedin S (NMS));

(24) SCD inhibitors;

(25) GPR-105 antagonists (e.g., such as those disclosed in WO2009/000087);

(26) SGLT inhibitors (e.g., ASP1941, SGLT-3, empagliflozin,dapagliflozin, canagliflozin, BI-10773, PF-04971729, remogloflozin,TS-071, tofogliflozin, ipragliflozin, and LX-4211);

(27) inhibitors of acyl coenzyme A:diacylglycerol acyltransferase 1 and2 (DGAT-1 and DGAT-2);

(28) inhibitors of fatty acid synthase;

(29) inhibitors of acyl coenzyme A:monoacylglycerol acyltransferase 1and 2 (MGAT-1 and MGAT-2);

(30) agonists of the TGR5 receptor (also known as GPBAR1, BG37, GPCR19,GPR131, and M-BAR);

(31) ileal bile acid transporter inhibitors;

(32) PACAP, PACAP mimetics, and PACAP receptor 3 agonists;

(33) PPAR agonists;

(34) protein tyrosine phosphatase-1B (PTP-1B) inhibitors;

(35) IL-1b antibodies, (e.g., XOMA052 and canakinumab);

(36) bromocriptine mesylate and rapid-release formulations thereof;

(37) GPR 120 agonists (such as KDT501.

Other suitable pharmaceutical agents of use in combination with acompound of the present invention, include, but are not limited to:

(a) anti-diabetic agents such as (1) PPARγ agonists such as glitazones(e.g. ciglitazone; darglitazone; englitazone; isaglitazone (MCC-555);pioglitazone (ACTOS); rosiglitazone (AVANDIA); troglitazone;rivoglitazone, BRL49653; CLX-0921; 5-BTZD, GW-0207, LG-100641, R483, andLY-300512, and the like and compounds disclosed in WO97/10813, 97/27857,97/28115, 97/28137, 97/27847, 03/000685, and 03/027112 and SPPARMS(selective PPAR gamma modulators) such as T131 (Amgen), FK614(Fujisawa), netoglitazone, and metaglidasen; (2) biguanides such asbuformin; metformin; and phenformin, and the like; (3) protein tyrosinephosphatase-1B (PTP-1B) inhibitors such as ISIS 113715, A-401674,A-364504, IDD-3, IDD 2846, KP-40046, KR61639, MC52445, MC52453, C7,OC-060062, OC-86839, OC29796, TTP-277BC1, and those agents disclosed inWO 04/041799, 04/050646, 02/26707, 02/26743, 04/092146, 03/048140,04/089918, 03/002569, 04/065387, 04/127570, and US 2004/167183; (4)sulfonylureas such as acetohexamide; chlorpropamide; diabinese;glibenclamide; glipizide; glyburide; glimepiride; gliclazide;glipentide; gliquidone; glisolamide; tolazamide; and tolbutamide, andthe like; (5) meglitinides such as repaglinide, metiglinide (GLUFAST)and nateglinide, and the like; (6) alpha glucoside hydrolase inhibitorssuch as acarbose; adiposine; camiglibose; emiglitate; miglitol;voglibose; pradimicin-Q; salbostatin; CKD-711; MDL-25,637; MDL-73,945;and MOR 14, and the like; (7) alpha-amylase inhibitors such astendamistat, trestatin, and A1-3688, and the like; (8) insulinsecreatagogues such as linogliride nateglinide, mitiglinide (GLUFAST),ID1101 A-4166, and the like; (9) fatty acid oxidation inhibitors, suchas clomoxir, and etomoxir, and the like; (10) A2 antagonists, such asmidaglizole; isaglidole; deriglidole; idazoxan; earoxan; and fluparoxan,and the like; (11) insulin or insulin mimetics, such as biota, LP-100,novarapid, insulin detemir, insulin lispro, insulin glargine, insulinzinc suspension (lente and ultralente); Lys-Pro insulin, GLP-1 (17-36),GLP-1 (73-7) (insulintropin); GLP-1 (7-36)-NH₂) exenatide/Exendin-4,Exenatide LAR, Linaglutide, AVE0010, CJC 1131, BIM51077, CS 872, THO318,BAY-694326, GP010, ALBUGON (GLP-1 fused to albumin), HGX-007 (Epacagonist), S-23521, and compounds disclosed in WO 04/022004, WO 04/37859,and the like; (12) non-thiazolidinediones such as JT-501, andfarglitazar (GW-2570/GI-262579), and the like; (13) PPARα/γ dualagonists such as AVE 0847, CLX-0940, GW-1536, GW1929, GW-2433, KRP-297,L-796449, LBM 642, LR-90, LY510919, MK-0767, ONO 5129, SB 219994,TAK-559, TAK-654, 677954 (GlaxoSmithkline), E-3030 (Eisai), LY510929(Lilly), AK109 (Asahi), DRF2655 (Dr. Reddy), DRF8351 (Dr. Reddy), MC3002(Maxocore), TY51501 (ToaEiyo), farglitazar, naveglitazar, muraglitazar,peliglitazar, tesaglitazar (GALIDA), reglitazar (JT-501), chiglitazar,and those disclosed in WO 99/16758, WO 99/19313, WO 99/20614, WO99/38850, WO 00/23415, WO 00/23417, WO 00/23445, WO 00/50414, WO01/00579, WO 01/79150, WO 02/062799, WO 03/033481, WO 03/033450, WO03/033453; and (14), insulin, insulin mimetics and other insulinsensitizing drugs; (15) VPAC2 receptor agonists; (16) GLK modulators,such as PSN105, RO 281675, RO 274375 and those disclosed in WO03/015774, WO 03/000262, WO 03/055482, WO 04/046139, WO 04/045614, WO04/063179, WO 04/063194, WO 04/050645, and the like; (17) retinoidmodulators such as those disclosed in WO 03/000249; (18) GSK 3beta/GSK 3inhibitors such as4-[2-(2-bromophenyl)-4-(4-fluorophenyl-1H-imidazol-5-yl]pyridine,CT21022, CT20026, CT-98023, SB-216763, SB410111, SB-675236, CP-70949,XD4241 and those compounds disclosed in WO 03/037869, 03/03877,03/037891, 03/024447, 05/000192, 05/019218 and the like; (19) glycogenphosphorylase (HGLPa) inhibitors, such as AVE 5688, PSN 357, GPi-879,those disclosed in WO 03/037864, WO 03/091213, WO 04/092158, WO05/013975, WO 05/013981, US 2004/0220229, and JP 2004-196702, and thelike; (20) ATP consumption promotors such as those disclosed in WO03/007990; (21) fixed combinations of PPAR γ agonists and metformin suchas AVANDAMET; (22) PPAR pan agonists such as GSK 677954; (23) GPR40(G-protein coupled receptor 40) also called SNORF 55 such as BG 700, andthose disclosed in WO 04/041266, 04/022551, 03/099793; (24) GPR119(G-protein coupled receptor 119, also called RUP3; SNORF 25) such asRUP3, HGPRBMY26, PFI 007, SNORF 25; (25) adenosine receptor 2Bantagonists such as ATL-618, ATl-802, E3080, and the like; (26)carnitine palmitoyl transferase inhibitors such as ST 1327, and ST 1326,and the like; (27) Fructose 1,6-bisphospohatase inhibitors such asCS-917, MB7803, and the like; (28) glucagon antagonists such as AT77077,BAY 694326, GW 4123X, NN2501, and those disclosed in WO 03/064404, WO05/00781, US 2004/0209928, US 2004/029943, and the like; (30)glucose-6-phosphase inhibitors; (31) phosphoenolpyruvate carboxykinase(PEPCK) inhibitors; (32) pyruvate dehydrogenase kinase (PDK) activators;(33) RXR agonists such as MC1036, CS00018, JNJ 10166806, and thosedisclosed in WO 04/089916, U.S. Pat. No. 6,759,546, and the like; (34)SGLT inhibitors such as AVE 2268, KGT 1251, T1095/RWJ 394718; (35)BLX-1002; (36) alpha glucosidase inhibitors; (37) glucagon receptoragonists; (38) glucokinase activators; 39) GIP-1; 40) insulinsecretagogues; 41) GPR-40 agonists, such as TAK-875,5-[4-[[(1R)-4-[6-(3-hydroxy-3-methylbutoxy)-2-methylpyridine-3-yl]-2,3-dihydro-1H-indene-1-yl]oxy]phenyl]is othiazole-3-ol 1-oxide,5-(4-((3-(2,6-dimethyl-4-(3-(methylsulfonyl)propoxy)phenyl)phenyl)methoxy)phenyl)iso,5-(4-((3-(2-methyl-6-(3-hydroxypropoxyl)pyridine-3-yl)-2-methylphenyl)methoxy)phenyl)isothiazole-3-ol1-oxide, and5-[4-[[3-[4-(3-aminopropoxy)-2,6-dimethylphenyl]phenyl]methoxy]phenyl]isothiazole-3-ol1-oxide), and those disclosed in WO 11/078371.

(b) anti-dyslipidemic agents such as (1) bile acid sequestrants such as,cholestyramine, colesevelem, colestipol, dialkylaminoalkyl derivativesof a cross-linked dextran; Colestid®; LoCholest®; and Questran®, and thelike; (2) HMG-CoA reductase inhibitors such as atorvastatin,itavastatin, pitavastatin, fluvastatin, lovastatin, pravastatin,rivastatin, simvastatin, rosuvastatin (ZD-4522), and other statins,particularly simvastatin; (3) HMG-CoA synthase inhibitors; (4)cholesterol absorption inhibitors such as FMVP4 (Forbes Medi-Tech),KT6-971 (Kotobuki Pharmaceutical), FM-VA12 (Forbes Medi-Tech), FM-VP-24(Forbes Medi-Tech), stanol esters, beta-sitosterol, sterol glycosidessuch as tiqueside; and azetidinones such as ezetimibe, and thosedisclosed in WO 04/005247 and the like; (5) acyl coenzyme A-cholesterolacyl transferase (ACAT) inhibitors such as avasimibe, eflucimibe,pactimibe (KY505), SMP 797 (Sumitomo), SM32504 (Sumitomo), and thosedisclosed in WO 03/091216, and the like; (6) CETP inhibitors such asanacetrapib, JTT 705 (Japan Tobacco), torcetrapib, CP 532,632,BAY63-2149 (Bayer), SC 591, SC 795, and the like; (7) squalenesynthetase inhibitors; (8) anti-oxidants such as probucol, and the like;(9) PPARα agonists such as beclofibrate, bezafibrate, ciprofibrate,clofibrate, etofibrate, fenofibrate, gemcabene, and gemfibrozil, GW7647, BM 170744 (Kowa), LY518674 (Lilly), GW590735 (GlaxoSmithkline),KRP-101 (Kyorin), DRF10945 (Dr. Reddy), NS-220/R1593 (NipponShinyaku/Roche, ST1929 (Sigma Tau) MC3001/MC3004 (MaxoCorePharmaceuticals, gemcabene calcium, other fibric acid derivatives, suchas Atromid®, Lopid® and Tricor®, and those disclosed in U.S. Pat. No.6,548,538, and the like; (10) FXR receptor modulators such as GW 4064(GlaxoSmithkline), SR 103912, QRX401, LN-6691 (Lion Bioscience), andthose disclosed in WO 02/064125, WO 04/045511, and the like; (11) LXRreceptor modulators such as GW 3965 (GlaxoSmithkline), T9013137, andXTCO179628 (X-Ceptor Therapeutics/Sanyo), and those disclosed in WO03/031408, WO 03/063796, WO 04/072041, and the like; (12) lipoproteinsynthesis inhibitors such as niacin; (13) renin angiotensin systeminhibitors; (14) PPAR δ partial agonists, such as those disclosed in WO03/024395; (15) bile acid reabsorption inhibitors, such as BARI 1453,SC435, PHA384640, S8921, AZD7706, and the like; and bile acidsequesterants such as colesevelam (WELCHOL/CHOLESTAGEL), colestipol,cholestyramine, and dialkylaminoalkyl derivatives of a cross-linkeddextran, (16) PPARδ agonists such as GW 501516 (Ligand, GSK), GW 590735,GW-0742 (GlaxoSmithkline), T659 (Amgen/Tularik), LY934 (Lilly),NNC610050 (Novo Nordisk) and those disclosed in WO97/28149, WO 01/79197,WO 02/14291, WO 02/46154, WO 02/46176, WO 02/076957, WO 03/016291, WO03/033493, WO 03/035603, WO 03/072100, WO 03/097607, WO 04/005253, WO04/007439, and JP10237049, and the like; (17) triglyceride synthesisinhibitors; (18) microsomal triglyceride transport (MTTP) inhibitors,such as implitapide, LAB687, JTT130 (Japan Tobacco), CP346086, and thosedisclosed in WO 03/072532, and the like; (19) transcription modulators;(20) squalene epoxidase inhibitors; (21) low density lipoprotein (LDL)receptor inducers; (22) platelet aggregation inhibitors; (23) 5-LO orFLAP inhibitors; and (24) niacin receptor agonists including HM74Areceptor agonists; (25) PPAR modulators such as those disclosed in WO01/25181, WO 01/79150, WO 02/79162, WO 02/081428, WO 03/016265, WO03/033453; (26) niacin-bound chromium, as disclosed in WO 03/039535;(27) substituted acid derivatives disclosed in WO 03/040114; (28)infused HDL such as LUV/ETC-588 (Pfizer), APO-A1 Milano/ETC216 (Pfizer),ETC-642 (Pfizer), ISIS301012, D4F (Bruin Pharma), synthetic trimericApoA1, Bioral Apo A1 targeted to foam cells, and the like; (29) IBATinhibitors such as BARI143/HMR145A/HMR1453 (Sanofi-Aventis, PHA384640E(Pfizer), 58921 (Shionogi) AZD7806 (AstrZeneca), AK105 (Asah Kasei), andthe like; (30) Lp-PLA2 inhibitors such as SB480848 (GlaxoSmithkline),659032 (GlaxoSmithkline), 677116 (GlaxoSmithkline), and the like; (31)other agents which affect lipic composition including ETC1001/ESP31015(Pfizer), ESP-55016 (Pfizer), AGI1067 (AtheroGenics), AC3056 (Amylin),AZD4619 (AstrZeneca); and

(c) anti-hypertensive agents such as (1) diuretics, such as thiazides,including chlorthalidone, chlorthiazide, dichlorophenamide,hydroflumethiazide, indapamide, and hydrochlorothiazide; loop diuretics,such as bumetanide, ethacrynic acid, furosemide, and torsemide;potassium sparing agents, such as amiloride, and triamterene; andaldosterone antagonists, such as spironolactone, epirenone, and thelike; (2) beta-adrenergic blockers such as acebutolol, atenolol,betaxolol, bevantolol, bisoprolol, bopindolol, carteolol, carvedilol,celiprolol, esmolol, indenolol, metaprolol, nadolol, nebivolol,penbutolol, pindolol, propanolol, sotalol, tertatolol, tilisolol, andtimolol, and the like; (3) calcium channel blockers such as amlodipine,aranidipine, azelnidipine, barnidipine, benidipine, bepridil,cinaldipine, clevidipine, diltiazem, efonidipine, felodipine,gallopamil, isradipine, lacidipine, lemildipine, lercanidipine,nicardipine, nifedipine, nilvadipine, nimodepine, nisoldipine,nitrendipine, manidipine, pranidipine, and verapamil, and the like; (4)angiotensin converting enzyme (ACE) inhibitors such as benazepril;captopril; cilazapril; delapril; enalapril; fosinopril; imidapril;losinopril; moexipril; quinapril; quinaprilat; ramipril; perindopril;perindropril; quanipril; spirapril; tenocapril; trandolapril, andzofenopril, and the like; (5) neutral endopeptidase inhibitors such asomapatrilat, cadoxatril and ecadotril, fosidotril, sampatrilat, AVE7688,ER4030, and the like; (6) endothelin antagonists such as tezosentan,A308165, and YM62899, and the like; (7) vasodilators such ashydralazine, clonidine, minoxidil, and nicotinyl alcohol, nicotinic acidor salt thereof, and the like; (8) angiotensin II receptor antagonistssuch as candesartan, eprosartan, irbesartan, losartan, pratosartan,tasosartan, telmisartan, valsartan, and EXP-3137, FI6828K, and RNH6270,and the like; (9) α/β adrenergic blockers as nipradilol, arotinolol andamosulalol, and the like; (10) alpha 1 blockers, such as terazosin,urapidil, prazosin, bunazosin, trimazosin, doxazosin, naftopidil,indoramin, WHIP 164, and XEN010, and the like; (11) alpha 2 agonistssuch as lofexidine, tiamenidine, moxonidine, rilmenidine and guanobenz,and the like; (12) aldosterone inhibitors, and the like; (13)angiopoietin-2-binding agents such as those disclosed in WO 03/030833;and

(d) anti-obesity agents, such as (1) 5HT (serotonin) transporterinhibitors, such as paroxetine, fluoxetine, fenfluramine, fluvoxamine,sertraline, and imipramine, and those disclosed in WO 03/00663, as wellas serotonin/noradrenaline re uptake inhibitors such as sibutramine(MERIDIA/REDUCTIL) and dopamine uptake inhibitor/Norepenephrine uptakeinhibitors such as radafaxine hydrochloride, 353162 (GlaxoSmithkline),and the like; (2) NE (norepinephrine) transporter inhibitors, such as GW320659, despiramine, talsupram, and nomifensine; (3) CB1 (cannabinoid-1receptor) antagonist/inverse agonists, such as taranabant, rimonabant(ACCOMPLIA Sanofi Synthelabo), SR-147778 (Sanofi Synthelabo), AVE1625(Sanofi-Aventis), BAY 65-2520 (Bayer), SLV 319 (Solvay), SLV326(Solvay), CP945598 (Pfizer), E-6776 (Esteve), 01691 (Organix), ORG14481(Organon), VER24343 (Vernalis), NESS0327 (Univ of Sassari/Univ ofCagliari), and those disclosed in U.S. Pat. Nos. 4,973,587, 5,013,837,5,081,122, 5,112,820, 5,292,736, 5,532,237, 5,624,941, 6,028,084, and6,509367; and WO 96/33159, WO97/29079, WO98/31227, WO 98/33765,WO98/37061, WO98/41519, WO98/43635, WO98/43636, WO99/02499, WO00/10967,WO00/10968, WO 01/09120, WO 01/58869, WO 01/64632, WO 01/64633, WO01/64634, WO 01/70700, WO 01/96330, WO 02/076949, WO 03/006007, WO03/007887, WO 03/020217, WO 03/026647, WO 03/026648, WO 03/027069, WO03/027076, WO 03/027114, WO 03/037332, WO 03/040107, WO 04/096763, WO04/111039, WO 04/111033, WO 04/111034, WO 04/111038, WO 04/013120, WO05/000301, WO 05/016286, WO 05/066126 and EP-658546 and the like; (4)ghrelin agonists/antagonists, such as BVT81-97 (BioVitrum), RC1291(Rejuvenon), SRD-04677 (Sumitomo), unacylated ghrelin(TheraTechnologies), and those disclosed in WO 01/87335, WO 02/08250, WO05/012331, and the like; (5) H3 (histamine H3) antagonist/inverseagonists, such as thioperamide, 3-(1H-imidazol-4-yl)propylN-(4-pentenyl)carbamate), clobenpropit, iodophenpropit, imoproxifan,GT2394 (Gliatech), and A331440, and those disclosed in WO 02/15905; andO-[3-(1H-imidazol-4-yl)propanol]carbamates (Kiec-Kononowicz, K. et al.,Pharmazie, 55:349-55 (2000)), piperidine-containing histamineH3-receptor antagonists (Lazewska, D. et al., Pharmazie, 56:927-32(2001), benzophenone derivatives and related compounds (Sasse, A. etal., Arch. Pharm. (Weinheim) 334:45-52 (2001)), substitutedN-phenylcarbamates (Reidemeister, S. et al., Pharmazie, 55:83-6 (2000)),and proxifan derivatives (Sasse, A. et al., J. Med. Chem. 43:3335-43(2000)) and histamine H3 receptor modulators such as those disclosed inWO 03/024928 and WO 03/024929; (6) melanin-concentrating hormone 1receptor (MCH1R) antagonists, such as T-226296 (Takeda), T71(Takeda/Amgen), AMGN-608450, AMGN-503796 (Amgen), 856464(GlaxoSmithkline), A224940 (Abbott), A798 (Abbott), ATC0175/AR224349(Arena Pharmaceuticals), GW803430 (GlaxoSmithkine), NBI-1A (NeurocrineBiosciences), NGX-1 (Neurogen), SNP-7941 (Synaptic), SNAP9847(Synaptic), T-226293 (Schering Plough), TPI-1361-17 (Saitama MedicalSchool/University of California Irvine), and those disclosed WO01/21169, WO 01/82925, WO 01/87834, WO 02/051809, WO 02/06245, WO02/076929, WO 02/076947, WO 02/04433, WO 02/51809, WO 02/083134, WO02/094799, WO 03/004027, WO 03/13574, WO 03/15769, WO 03/028641, WO03/035624, WO 03/033476, WO 03/033480, WO 04/004611, WO 04/004726, WO04/011438, WO 04/028459, WO 04/034702, WO 04/039764, WO 04/052848, WO04/087680; and Japanese Patent Application Nos. JP 13226269, JP 1437059,JP2004315511, and the like; (7) MCH2R (melanin concentrating hormone 2R)agonist/antagonists; (8) NPY1 (neuropeptide Y Y1) antagonists, such asBMS205749, BIBP3226, J-115814, BIBO 3304, LY-357897, CP-671906, andGI-264879A; and those disclosed in U.S. Pat. No. 6,001,836; and WO96/14307, WO 01/23387, WO 99/51600, WO 01/85690, WO 01/85098, WO01/85173, and WO 01/89528; (9) NPY5 (neuropeptide Y Y5) antagonists,such as 152,804, 52367 (Shionogi), E-6999 (Esteve), GW-569180A,GW-594884A (GlaxoSmithkline), GW-587081X, GW-548118X; FR 235,208;FR226928, FR 240662, FR252384; 1229U91, GI-264879A, CGP71683A, C-75(Fasgen) LY-377897, LY366377, PD-160170, SR-120562A, SR-120819A, S2367(Shionogi), JCF-104, and H409/22; and those compounds disclosed in U.S.Pat. Nos. 6,140,354, 6,191,160, 6,258,837, 6,313,298, 6,326,375,6,329,395, 6,335,345, 6,337,332, 6,329,395, and 6,340,683; andEP-01010691, EP-01044970, and FR252384; and PCT Publication Nos. WO97/19682, WO 97/20820, WO 97/20821, WO 97/20822, WO 97/20823, WO98/27063, WO 00/107409, WO 00/185714, WO 00/185730, WO 00/64880, WO00/68197, WO 00/69849, WO 01/09120, WO 01/14376, WO 01/85714, WO01/85730, WO 01/07409, WO 01/02379, WO 01/02379, WO 01/23388, WO01/23389, WO 01/44201, WO 01/62737, WO 01/62738, WO 01/09120, WO02/20488, WO 02/22592, WO 02/48152, WO 02/49648, WO 02/051806, WO02/094789, WO 03/009845, WO 03/014083, WO 03/022849, WO 03/028726, WO05/014592, WO 05/01493; and Norman et al., J. Med. Chem. 43:4288-4312(2000); (10) leptin, such as recombinant human leptin (PEG-OB, HoffmanLa Roche) and recombinant methionyl human leptin (Amgen); (11) leptinderivatives, such as those disclosed in U.S. Pat. Nos. 5,552,524;5,552,523; 5,552,522; 5,521,283; and WO 96/23513; WO 96/23514; WO96/23515; WO 96/23516; WO 96/23517; WO 96/23518; WO 96/23519; and WO96/23520; (12) opioid antagonists, such as nalmefene (Revex®),3-methoxynaltrexone, naloxone, and naltrexone; and those disclosed in WO00/21509; (13) orexin antagonists, such as SB-334867-A(GlaxoSmithkline); and those disclosed in WO 01/96302, 01/68609,02/44172, 02/51232, 02/51838, 02/089800, 02/090355, 03/023561,03/032991, 03/037847, 04/004733, 04/026866, 04/041791, 04/085403, andthe like; (14) BRS3 (bombesin receptor subtype 3) agonists; (15) CCK-A(cholecystokinin-A) agonists, such as AR-R 15849, GI 181771, JMV-180,A-71378, A-71623, PD170292, PD 149164, SR146131, SR125180, butabindide,and those disclosed in U.S. Pat. No. 5,739,106; (16) CNTF (ciliaryneurotrophic factors), such as GI-181771 (Glaxo-SmithKline); SR146131(Sanofi Synthelabo); butabindide; and PD170,292, PD 149164 (Pfizer);(17) CNTF derivatives, such as axokine (Regeneron); and those disclosedin WO 94/09134, WO 98/22128, and WO 99/43813; (18) GHS (growth hormonesecretagogue receptor) agonists, such as NN703, hexarelin, MK-0677,SM-130686, CP-424,391, L-692,429 and L-163,255, and those disclosed inU.S. Pat. No. 6,358,951, U.S. Patent Application Nos. 2002/049196 and2002/022637; and WO 01/56592, and WO 02/32888; (19) 5HT2c (serotoninreceptor 2c) agonists, such as APD3546/AR10A (Arena Pharmaceuticals),ATH88651 (Athersys), ATH88740 (Athersys), BVT933 (Biovitrum/GSK),DPCA37215 (BMS), IK264; LY448100 (Lilly), PNU 22394; WAY 470 (Wyeth),WAY629 (Wyeth), WAY161503 (Biovitrum), R-1065, VR1065 (Vernalis/Roche)YM 348; and those disclosed in U.S. Pat. No. 3,914,250; and PCTPublications 01/66548, 02/36596, 02/48124, 02/10169, 02/44152; 02/51844,02/40456, 02/40457, 03/057698, 05/000849, and the like; (20) Mc3r(melanocortin 3 receptor) agonists; (21) Mc4r (melanocortin 4 receptor)agonists, such as CHIR86036 (Chiron), CHIR915 (Chiron); ME-10142(Melacure), ME-10145 (Melacure), HS-131 (Melacure), NBI72432 (NeurocrineBiosciences), NNC 70-619 (Novo Nordisk), TTP2435 (Transtech) and thosedisclosed in PCT Publications WO 99/64002, 00/74679, 01/991752,01/0125192, 01/52880, 01/74844, 01/70708, 01/70337, 01/91752, 01/010842,02/059095, 02/059107, 02/059108, 02/059117, 02/062766, 02/069095,02/12166, 02/11715, 02/12178, 02/15909, 02/38544, 02/068387, 02/068388,02/067869, 02/081430, 03/06604, 03/007949, 03/009847, 03/009850,03/013509, 03/031410, 03/094918, 04/028453, 04/048345, 04/050610,04/075823, 04/083208, 04/089951, 05/000339, and EP 1460069, and US2005049269, and JP2005042839, and the like; (22) monoamine reuptakeinhibitors, such as sibutratmine (Meridia®/Reductil®) and salts thereof,and those compounds disclosed in U.S. Pat. Nos. 4,746,680, 4,806,570,and 5,436,272, and U.S. Patent Publication No. 2002/0006964, and WO01/27068, and WO 01/62341; (23) serotonin reuptake inhibitors, such asdexfenfluramine, fluoxetine, and those in U.S. Pat. No. 6,365,633, andWO 01/27060, and WO 01/162341; (24) GLP-1 (glucagon-like peptide 1)agonists; (25) Topiramate (Topimax®); (26) phytopharm compound 57 (CP644,673); (27) ACC2 (acetyl-CoA carboxylase-2) inhibitors; (28) β3 (betaadrenergic receptor 3) agonists, such as rafebergron/AD9677/TAK677(Dainippon/Takeda), CL-316,243, SB 418790, BRL-37344, L-796568,BMS-196085, BRL-35135A, CGP12177A, BTA-243, GRC1087 (GlenmarkPharmaceuticals) GW 427353 (solabegron hydrochloride), Trecadrine,Zeneca D7114, N-5984 (Nisshin Kyorin), LY-377604 (Lilly), KT07924(Kissei), SR 59119A, and those disclosed in U.S. Pat. No. 5,705,515,U.S. Pat. No. 5,451,677; and WO94/18161, WO95/29159, WO97/46556,WO98/04526 WO98/32753, WO 01/74782, WO 02/32897, WO 03/014113, WO03/016276, WO 03/016307, WO 03/024948, WO 03/024953, WO 03/037881, WO04/108674, and the like; (29) DGAT1 (diacylglycerol acyltransferase 1)inhibitors; (30) DGAT2 (diacylglycerol acyltransferase 2) inhibitors;(31) FAS (fatty acid synthase) inhibitors, such as Cerulenin and C75;(32) PDE (phosphodiesterase) inhibitors, such as theophylline,pentoxifylline, zaprinast, sildenafil, amrinone, milrinone, cilostamide,rolipram, and cilomilast, as well as those described in WO 03/037432, WO03/037899; (33) thyroid hormone β agonists, such as KB-2611(KaroBioBMS), and those disclosed in WO 02/15845; and Japanese PatentApplication No. JP 2000256190; (34) UCP-1 (uncoupling protein 1), 2, or3 activators, such as phytanic acid,4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-napthalenyl)-1-propenyl]benzoicacid (TTNPB), and retinoic acid; and those disclosed in WO 99/00123;(35) acyl-estrogens, such as oleoyl-estrone, disclosed in del Mar-Grasa,M. et al., Obesity Research, 9:202-9 (2001); (36) glucocorticoidreceptor antagonists, such as CP472555 (Pfizer), KB 3305, and thosedisclosed in WO 04/000869, WO 04/075864, and the like; (37) 11β HSD-1(11-beta hydroxy steroid dehydrogenase type 1) inhibitors, such as BVT3498 (AMG 331), BVT 2733,3-(1-adamantyl)-4-ethyl-5-(ethylthio)-4H-1,2,4-triazole,3-(1-adamantyl)-5-(3,4,5-trimethoxyphenyl)-4-methyl-4H-1,2,4-triazole,3-adamantanyl-4,5,6,7,8,9,10,11,12,3a-decahydro-1,2,4-triazolo[4,3-a][11]annulene,and those compounds disclosed in WO 01/90091, 01/90090, 01/90092,02/072084, 04/011410, 04/033427, 04/041264, 04/027047, 04/056744,04/065351, 04/089415, 04/037251, and the like; (38) SCD-1 (stearoyl-CoAdesaturase-1) inhibitors; (39) dipeptidyl peptidase IV (DPP-4)inhibitors, such as isoleucine thiazolidide, valine pyrrolidide,sitagliptin (Januvia), saxagliptin, alogliptin, NVP-DPP728, LAF237(vildagliptin), P93/01, TSL 225, TMC-2A/2B/2C, FE 999011, P9310/K364,VIP 0177, SDZ 274-444, GSK 823093, E 3024, SYR 322, TS021, SSR 162369,GRC 8200, K579, NN7201, CR 14023, PHX 1004, PHX 1149, PT-630, SK-0403;and the compounds disclosed in WO 02/083128, WO 02/062764, WO 02/14271,WO 03/000180, WO 03/000181, WO 03/000250, WO 03/002530, WO 03/002531, WO03/002553, WO 03/002593, WO 03/004498, WO 03/004496, WO 03/005766, WO03/017936, WO 03/024942, WO 03/024965, WO 03/033524, WO 03/055881, WO03/057144, WO 03/037327, WO 04/041795, WO 04/071454, WO 04/0214870, WO04/041273, WO 04/041820, WO 04/050658, WO 04/046106, WO 04/067509, WO04/048532, WO 04/099185, WO 04/108730, WO 05/009956, WO 04/09806, WO05/023762, US 2005/043292, and EP 1 258 476; (40) lipase inhibitors,such as tetrahydrolipstatin (orlistat/XENICAL), ATL962 (Alizyme/Takeda),GT389255 (Genzyme/Peptimmune) Triton WR1339, RHC80267, lipstatin,teasaponin, and diethylumbelliferyl phosphate, FL-386, WAY-121898,Bay-N-3176, valilactone, esteracin, ebelactone A, ebelactone B, and RHC80267, and those disclosed in WO 01/77094, WO 04/111004, and U.S. Pat.Nos. 4,598,089, 4,452,813, 5,512,565, 5,391,571, 5,602,151, 4,405,644,4,189,438, and 4,242,453, and the like; (41) fatty acid transporterinhibitors; (42) dicarboxylate transporter inhibitors; (43) glucosetransporter inhibitors; and (44) phosphate transporter inhibitors; (45)anorectic bicyclic compounds such as 1426 (Aventis) and 1954 (Aventis),and the compounds disclosed in WO 00/18749, WO 01/32638, WO 01/62746, WO01/62747, and WO 03/015769; (46) peptide YY and PYY agonists such asPYY336 (Nastech/Merck), AC162352 (IC Innovations/Curis/Amylin),TM30335/TM30338 (7TM Pharma), PYY336 (Emisphere Tehcnologies), pegylatedpeptide YY3-36, those disclosed in WO 03/026591, 04/089279, and thelike; (47) lipid metabolism modulators such as maslinic acid,erythrodiol, ursolic acid uvaol, betulinic acid, betulin, and the likeand compounds disclosed in WO 03/011267; (48) transcription factormodulators such as those disclosed in WO 03/026576; (49) Mc5r(melanocortin 5 receptor) modulators, such as those disclosed in WO97/19952, WO 00/15826, WO 00/15790, US 20030092041, and the like; (50)Brain derived neutotropic factor (BDNF), (51) Mc1r (melanocortin 1receptor modulators such as LK-184 (Proctor & Gamble), and the like;(52) 5HT6 antagonists such as BVT74316 (BioVitrum), BVT5182c(BioVitrum), E-6795 (Esteve), E-6814 (Esteve), SB399885(GlaxoSmithkline), SB271046 (GlaxoSmithkline), RO-046790 (Roche), andthe like; (53) fatty acid transport protein 4 (FATP4); (54) acetyl-CoAcarboxylase (ACC) inhibitors such as CP640186, CP610431, CP640188(Pfizer); (55)C-terminal growth hormone fragments such as AOD9604(Monash Univ/Metabolic Pharmaceuticals), and the like; (56)oxyntomodulin; (57) neuropeptide FF receptor antagonists such as thosedisclosed in WO 04/083218, and the like; (58) amylin agonists such asSymlin/pramlintide/AC137 (Amylin); (59) Hoodia and trichocaulonextracts; (60) BVT74713 and other gut lipid appetite suppressants; (61)dopamine agonists such as bupropion (WELLBUTRIN/GlaxoSmithkline); (62)zonisamide (ZONEGRAN/Dainippon/Elan), and the like; and

(e) anorectic agents suitable for use in combination with a compound ofthe present invention include, but are not limited to, aminorex,amphechloral, amphetamine, benzphetamine, chlorphentermine, clobenzorex,cloforex, clominorex, clortermine, cyclexedrine, dexfenfluramine,dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine,fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex,fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane,mazindol, mefenorex, metamfepramone, methamphetamine,norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine,phentermine, phenylpropanolamine, picilorex and sibutramine; andpharmaceutically acceptable salts thereof. A particularly suitable classof anorectic agent are the halogenated amphetamine derivatives,including chlorphentermine, cloforex, clortermine, dexfenfluramine,fenfluramine, picilorex and sibutramine; and pharmaceutically acceptablesalts thereof. Particular halogenated amphetamine derivatives of use incombination with a compound of the present invention include:fenfluramine and dexfenfluramine, and pharmaceutically acceptable saltsthereof.

Specific compounds of use in combination with a compound of the presentinvention include: simvastatin, mevastatin, ezetimibe, atorvastatin,sitagliptin, metformin, sibutramine, orlistat, Qnexa, topiramate,naltrexone, bupriopion, phentermine, and losartan, losartan withhydrochlorothiazide. Specific CB1 antagonists/inverse agonists of use incombination with a compound of the present invention include: thosedescribed in WO03/077847, including:N-[3-(4-chlorophenyl)-2(S)-phenyl-1(S)-methylpropyl]-2-(4-trifluoromethyl-2-pyrimidyloxy)-2-methylpropanamide,N-[3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,N-[3-(4-chlorophenyl)-2-(5-chloro-3-pyridyl)-1-methylpropyl]-2-(5-trifluoromethyl-2-pyridyloxy)-2-methylpropanamide,and pharmaceutically acceptable salts thereof; as well as those inWO05/000809, which includes the following:3-{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-3-(3,5-difluorophenyl)-2,2-dimethylpropanenitrile,1-{1-[1-(4-chlorophenyl)pentyl]azetidin-3-yl}-1-(3,5-difluorophenyl)-2-methylpropan-2-ol.3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-hydroxy-2-methylpropyl]azetidin-1-yl}methyl)benzonitrile,3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)benzonitrile,3-((4-chlorophenyl){3-[1-(3,5-difluorophenyl)-2,2-dimethylpropyl]azetidin-1-yl}methyl)benzonitrile,3-((1S)-1-{1-[(S)-(3-cyanophenyl)(4-cyanophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile,3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(4H-1,2,4-triazol-4-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,and 5-((4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)thiophene-3-carbonitrile,and pharmaceutically acceptable salts thereof; as well as:3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(S)-(3-{(1S)-1-[3-(5-amino-1,3,4-oxadiazol-2-yl)-5-fluorophenyl]-2-fluoro-2-methylpropyl}azetidin-1-yl)(4-chlorophenyl)methyl]benzonitrile,3-[(S)-(4-cyanophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(S)-(3-{(1S)-1-[3-(5-amino-1,3,4-oxadiazol-2-yl)-5-fluorophenyl]-2-fluoro-2-methylpropyl}azetidin-1-yl)(4-cyanophenyl)methyl]benzonitrile,3-[(S)-(4-cyanophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(1,3,4-oxadiazol-2-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(S)-(4-chlorophenyl)(3-{(1S)-2-fluoro-1-[3-fluoro-5-(1,2,4-oxadiazol-3-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(1,2,4-oxadiazol-3-yl)phenyl]-methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,5-(3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorophenyl)-1H-tetrazole,5-(3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorophenyl)-1-methyl-1H-tetrazole,5-(3-{1-[1-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl}-5-fluorophenyl)-2-methyl-2H-tetrazole,3-[(4-chlorophenyl)(3-{2-fluoro-1-[3-fluoro-5-(2-methyl-2H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(4-chlorophenyl)(3-{2-fluoro-1-[3-fluoro-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(4-cyanophenyl)(3-{2-fluoro-1-[3-fluoro-5-(1-methyl-1H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,3-[(4-cyanophenyl)(3-{2-fluoro-1-[3-fluoro-5-(2-methyl-2H-tetrazol-5-yl)phenyl]-2-methylpropyl}azetidin-1-yl)methyl]benzonitrile,5-{3-[(S)-{3-[(1S)-1-(3-bromo-5-fluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}(4-chlorophenyl)methyl]phenyl}-1,3,4-oxadiazol-2(3H)-one,3-[(1S)-1-(1-{(S)-(4-chlorophenyl)[3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,3-[(1S)-1-(1-{(S)-(4-chlorophenyl)[3-(1,3,4-oxadiazol-2-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,3-((1S)-1-{1-[(S)-[3-(5-amino-1,3,4-oxadiazol-2-yl)phenyl](4-chlorophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile,3-((1S)-1-{1-[(S)-[3-(5-amino-1,3,4-oxadiazol-2-yl)phenyl](4-cyanophenyl)methyl]azetidin-3-yl}-2-fluoro-2-methylpropyl)-5-fluorobenzonitrile,3-[(1S)-1-(1-{(S)-(4-cyanophenyl)[3-(1,2,4-oxadiazol-3-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,3-[(1S)-1-(1-{(S)-(4-chlorophenyl)[3-(1,2,4-oxadiazol-3-yl)phenyl]methyl}azetidin-3-yl)-2-fluoro-2-methylpropyl]-5-fluorobenzonitrile,5-[3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)phenyl]-1,3,4-oxadiazol-2(3H)-one,5-[3-((S)-(4-chlorophenyl){3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}methyl)phenyl]-1,3,4-oxadiazol-2(3H)-one,4-{(S)-{3-[(1S)-1-(3,5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}[3-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)phenyl]methyl}-benzonitrile,and pharmaceutically acceptable salts thereof.

Specific NPY5 antagonists of use in combination with a compound of thepresent invention include:3-oxo-N-(5-phenyl-2-pyrazinyl)-spiro[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,3-oxo-N-(7-trifluoromethylpyrido[3,2-b]pyridin-2-yl)spiro-[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro-[isobenzofuran-1(3H),4′-piperidine]-1′-carboxamide,trans-3′-oxo-N-(5-phenyl-2-pyrimidinyl)spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,trans-3′-oxo-N-[1-(3-quinolyl)-4-imidazolyl]spiro[cyclohexane-1,1′(3′H)-isobenzofuran]-4-carboxamide,trans-3-oxo-N-(5-phenyl-2-pyrazinyl)spiro[4-azaiso-benzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[5-(3-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[5-(2-fluorophenyl)-2-pyrimidinyl]-3-oxospiro[5-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[1-(3,5-difluorophenyl)-4-imidazolyl]-3-oxospiro[7-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(1-phenyl-4-pyrazolyl)spiro[4-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-N-[1-(2-fluorophenyl)-3-pyrazolyl]-3-oxospiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(1-phenyl-3-pyrazolyl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,trans-3-oxo-N-(2-phenyl-1,2,3-triazol-4-yl)spiro[6-azaisobenzofuran-1(3H),1′-cyclohexane]-4′-carboxamide,and pharmaceutically acceptable salts and esters thereof.

Specific ACC-1/2 inhibitors of use in combination with a compound of thepresent invention include:l′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one;(5-{1′-[(4,8-dimethoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}-2H-tetrazol-2-yl)methylpivalate;5-{l′-[(8-cyclopropyl-4-methoxyquinolin-2-yl)carbonyl]-4-oxospiro[chroman-2,4′-piperidin]-6-yl}nicotinicacid;1′-(8-methoxy-4-morpholin-4-yl-2-naphthoyl)-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one;and1′-[(4-ethoxy-8-ethylquinolin-2-yl)carbonyl]-6-(1H-tetrazol-5-yl)spiro[chroman-2,4′-piperidin]-4-one;and pharmaceutically acceptable salts and esters thereof. Specific MCH1Rantagonist compounds of use in combination with a compound of thepresent invention include:1-{4-[(1-ethylazetidin-3-yl)oxy]phenyl}-4-[(4-fluorobenzyl)oxy]pyridin-2(1H)-one,4-[(4-fluorobenzyl)oxy]-1-{4-[(1-isopropylazetidin-3-yl)oxy]phenyl}pyridin-2(1H)-one,1-[4-(azetidin-3-yloxy)phenyl]-4-[(5-chloropyridin-2-yl)methoxy]pyridin-2(1H)-one,4-[(5-chloropyridin-2-yl)methoxy]-1-{4-[(1-ethylazetidin-3-yl)oxy]phenyl}pyridin-2(1H)-one,4-[(5-chloropyridin-2-yl)methoxy]-1-{4-[(1-propylazetidin-3-yl)oxy]phenyl}pyridin-2(1H)-one,and4-[(5-chloropyridin-2-yl)methoxy]-1-(4-{[(2S)-1-ethylazetidin-2-yl]methoxy}phenyl)pyridin-2(1H)-one,or a pharmaceutically acceptable salt thereof.

Specific DP-IV inhibitors of use in combination with a compound of thepresent invention are selected from Januvia,7-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine.In particular, the compound of formula I is favorably combined with7-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrazine,and pharmaceutically acceptable salts thereof.

Specific H3 (histamine H3) antagonists/inverse agonists of use incombination with a compound of the present invention include: thosedescribed in WO05/077905, including:3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[2,3-d]-pyrimidin-4(3H)-one,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one,2-ethyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2,5-dimethyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-methyl-5-trifluoromethyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-5-methoxy-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-5-fluoro-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-7-fluoro-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-methoxy-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-fluoro-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-8-fluoro-2-methyl-4(3H)-quinazolinone,3-{4-[(1-cyclopentyl-4-piperidinyl)oxy]phenyl}-2-methylpyrido[4,3-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}-6-fluoro-2-methylpyrido[3,4-d]pyrimidin-4(3H)-one,3-{4-[(1-cyclobutyl-4-piperidinyl)oxy]phenyl}-2-ethylpyrido[4,3-d]pyrimidin-4(3H)-one,6-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4(3H)-one,6-methoxy-2-methyl-3-{4-[3-(1-pyrrol idinyl)propoxy]phenyl}pyrido[3,4-d]pyrimidin-4 (3H)-one,2,5-dimethyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-4(3H)-quinazolinone,2-methyl-3-{4-[3-(1-pyrrolidinyl)propoxy]phenyl}-5-trifluoromethyl-4(3H)-quinazolinone,5-fluoro-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,6-methoxy-2-methyl-3-{4-[3-(1-piperidinyl)propoxy]phenyl}-4(3H)-quinazolinone,5-methoxy-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,7-methoxy-2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,2-methyl-3-(4-{3-[(3S)-3-methylpiperidin-1-yl]propoxy}phenyl)pyrido[2,3-d]pyrimidin-4(3H)-one,5-fluoro-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)pyrido[4,3-d]pyrimidin-4(3H)-one,6-methoxy-2-methyl-3-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,6-methoxy-2-methyl-3-(4-{3-[(2S)-2-methylpyrrolidin-1-yl]propoxy}phenyl)-4(3H)-quinazolinone,and pharmaceutically acceptable salts thereof.

Specific CCK1R agonists of use in combination with a compound of thepresent invention include:3-(4-{[1-(3-ethoxyphenyl)-2-(4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid;3-(4-{[1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid;3-(4-{[1-(3-ethoxyphenyl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid;3-(4-{[1-(3-ethoxyphenyl)-2-(2,4-difluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid; and3-(4-{[1-(2,3-dihydro-1,4-benzodioxin-6-yl)-2-(4-fluorophenyl)-1H-imidazol-4-yl]carbonyl}-1-piperazinyl)-1-naphthoicacid; and pharmaceutically acceptable salts thereof.

Specific MC4R agonists of use in combination with a compound of thepresent invention include: 1) (5S)-1′-{[(3R,4R)-1-tert-butyl-3-(2,3,4-trifluorophenyl)piperidin-4-yl]carbonyl}-3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine];2)(5R)-1′-{[(3R,4R)-1-tert-butyl-3-(2,3,4-trifluorophenyl)-piperidin-4-yl]carbonyl}-3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine];3)2-(1′-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-3-chloro-2-methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-yl)-2-methylpropanenitrile;4)1′-{[(3S,4R)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidine];5)N-[(3R,4R)-3-({3-chloro-2-methyl-5-[1-methyl-1-(1-methyl-1H-1,2,4-triazol-5-yl)ethyl]-1′H,5H-spiro[furo-[3,4-b]pyridine-7,4′-piperidin]-1′-yl}carbonyl)-4-(2,4-difluorophenyl)-cyclopentyl]-N-methyltetrahydro-2H-pyran-4-amine;6)2-[3-chloro-1′-({(1R,2R)-2-(2,4-difluorophenyl)-4-[methyl(tetrahydro-2H-pyran-4-yl)amino]-cyclopentyl}-carbonyl)-2-methyl-5H-spiro[furo[3,4-b]pyridine-7,4′-piperidin]-5-yl]-2-methyl-propane-nitrile;and pharmaceutically acceptable salts thereof.

Suitable neurokinin-1 (NK-1) receptor antagonists may be favorablyemployed with the AMP-kinase activators of the present invention. NK-1receptor antagonists of use in the present invention are fully describedin the art. Specific neurokinin-1 receptor antagonists of use in thepresent invention include:(±)-(2R3R,2S3S)—N-{[2-cyclopropoxy-5-(trifluoromethoxy)-phenyl]methyl}-2-phenylpiperidin-3-amine;2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)-phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methyl)morpholine;aperpitant; CJ17493; GW597599; GW679769; R673; RO67319; R1124; R1204;SSR146977; SSR240600; T-2328; and T2763; or a pharmaceuticallyacceptable salts thereof.

The term “therapeutically effective amount” means the amount thecompound of structural formula I that will elicit the biological ormedical response of a tissue, system, animal or human that is beingsought by the researcher, veterinarian, medical doctor or otherclinician, which includes alleviation of the symptoms of the disorderbeing treated. The novel methods of treatment of this invention are fordisorders known to those skilled in the art. The term “mammal” includeshumans, and companion animals such as dogs and cats.

The weight ratio of the compound of the Formula I to the second activeingredient may be varied and will depend upon the effective dose of eachingredient. Generally, an effective dose of each will be used. Thus, forexample, when a compound of the Formula I is combined with a DPIVinhibitor the weight ratio of the compound of the Formula I to the DPIVinhibitor will generally range from about 1000:1 to about 1:1000,preferably about 200:1 to about 1:200. Combinations of a compound of theFormula I and other active ingredients will generally also be within theaforementioned range, but in each case, an effective dose of each activeingredient should be used.

The compounds of structural formula I of the present invention can beprepared according to the procedures of the following Schemes,Intermediates and Examples, using appropriate materials and are furtherexemplified by the following specific examples. Moreover, by utilizingthe procedures described in the disclosure contained herein, one ofordinary skill in the art can readily prepare additional compounds ofthe present invention claimed herein. The compounds illustrated in theexamples are not, however, to be construed as forming the only genusthat is considered as the invention. The Examples further illustratedetails for the preparation of the compounds of the present invention.Those skilled in the art will readily understand that known variationsof the conditions and processes of the following preparative procedurescan be used to prepare these compounds. The instant compounds aregenerally isolated in the form of their pharmaceutically acceptablesalts, such as those previously described herein. The use of protectinggroups for the amine and carboxylic acid functionalities to facilitatethe desired reaction and minimize undesired reactions is welldocumented. Conditions required to remove protecting groups are found instandard textbooks such as Greene, T, and Wuts, P. G. M., ProtectiveGroups in Organic Synthesis, John Wiley & Sons, Inc., New York, N.Y.,1991. CBZ and BOC are commonly used protecting groups in organicsynthesis, and their removal conditions are known to those skilled inthe art. All temperatures are degrees Celsius unless otherwise noted.Mass spectra (MS) were measured by electron-spray ion-mass spectroscopy.

Abbreviations used in the description of the preparation of thecompounds of the present invention: ACN is acetonitrile; AcOH is aceticacid; aq or aq. is aqueous; Boc₂O is t-butoxycarbonyl anhydride; n-BuLiis n-butyllithium; C is carbon; CPME is cyclopentyl methyl ether; CV iscolumn volume(s); DAST is (diethylamino)sulfur trifluoride; DBU is1,8-diazabicyclo[5.4.0]-undec-7-ene; DIBAL-H is di-isobutyl aluminumhydride; DCE is dichloroethane; DCM is dichloromethane; DEAD is diethylazodicarboxylate; DIAD is diisopropyl azodicarboxylate; DIEA and DIPEAis diisopropylethyl amine; DMA is dimethyl acetal; DMAP is4-(Dimethylamino)pyridine; DME is 1,2-dimethoxyethane; DMF is dimethylformamide; DMSO is dimethyl sulfoxide; dppf DCM complex is1,1′-bis(diphenyl-phosphino)ferrocene dichloromethane complex; DPPP isdiphenyl phosphinopropane; EDC isN-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide; Et₂O is diethyl ether;EtOAc is ethyl acetate; dppf is 1,1′-Bis(diphenyl-phosphino)ferrocene;EtOH is ethanol; Et₃N is triethyl amine; h is hour(s); HATU isO-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate; Hex or hex is hexanes; HOBT is1-Hydroxybenzotriazole; HPLC is high pressure liquid chromatography;ISCO R_(f) is the R^(f) determined via medium pressure liquidchromatography using a Teledyne ISCO RediSep® column; isomannide is1,4:3,6-Di-anhydro-mannitol; KOAc is potassium acetate; L is liter;LC/MS and LC-MS is liquid chromatography/mass spectroscopy; KOTMS ispotassium trimethylsilanolate; LAH is lithium aluminum hydride; M ismolar; ml and mL is milliliter; Me is methyl, MeCN is acetonitrile; MeIis methyl iodide; MeMgBr is methyl magnesium bromide; MeOH is methanol;MgBr is magnesium bromide; min is minutes; mmol is millimole(s); m-CPBAis meta chloro per benzoic acid; MPLC is medium pressure liquidchromatography; MS is molecular sieves; MTBE is tert-butyl methyl ether;N is normal; NaOAc is sodium acetate; NBS is N-bromo succinamide; NIS isN-iodo succinamide; Pd₂(dba)₃ istris(dibenzylideneacetone)-dipalladium(0); [PdCl₂(dppf)]CH₂Cl₂ orPdCl₂(dppf)-DCM is1,1′-Bis(diphenylphosphino)-ferrocene-palladium(II)dichloridedichloromethane complex; PPh₃ is triphenyl phosphine; PhSiH is phenylsilane; wt % is weight percent; psi is pounds per square inch; RT and rtis room temperature; Rt is retention time; Rochelles' Salt is potassiumsodium tartrate; RuPhos is2-Dicyclohexyl-phosphino-2′,6′-diisopropoxybiphenyl; sat or sat. issaturated; SEM is 2-(trimethylsilyl)ethoxymethyl; SEM-C1 and SEMC1 is2-(trimethylsilyl)-ethoxymethyl chloride; TBAF is tetrabutyl ammoniumfluoride; TBSCl and TBDMSCl is ten-butyldimethylsilyl chloride; TEA istriethylamine; TESCl is chlorotriethylsilane; TFA is trifluoro aceticacid; THF is tetrahydrofuran; TMS is trimethylsilyl; Tosyl-Cl isp-toluene-sulfonyl chloride; and XPhos is2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl.

Microwave (MW) reactions were performed with a single mode operatingBiotage Emrys Optimizer in sealed reaction vials at the indicated fixedtemperature held constant for the designated reaction time. The mediumpressure liquid chromatography (MPLC) purifications were performed withTeledyne ISCO RediSep® normal-phase columns pre-packed with 35-60 micronsilica gel. The LC-MS system contained an Applied Biosystems API150EX MSoperating in a positive ion mode receiving 0.1 mL/min flowrate with aShimadzu UV detector receiving 0.1 mL/min flowrate. Unless specified,the LC conditions were solvent A=0.05% TFA in acetonitrile; solventB=0.05% TFA in water; flowrate=10 mL/min; column: Chromolith PerformanceRP-18e, 100×4.6 mm. Unless specified, the ¹H NMRs were obtained in CD₃ODat 500 MHz and spectra were recorded in units δ. C, H, N microanalyseswere performed by Robertson Microlit Laboratories, Inc., Madison, N.J.

The following reaction schemes illustrate methods which may be employedfor the synthesis of the compounds of structural formula I described inthis invention. All substituents are as defined above unless indicatedotherwise. Several strategies based upon synthetic transformations knownin the literature of organic synthesis may be employed for thepreparation of the compounds of general formula I.

Intermediate 1

6-chloro-5-iodo-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole

A reaction vessel was charged with(4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-ol (0.534 g,2.260 mmol),6-chloro-5-iodo-2-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole(1 g, 2.054 mmol) and cesium carbonate (1.339 g, 4.11 mmol) and thesolids were dissolved in DMF (8.22 ml). The reaction mixture was stirred18 h at rt, then diluted with EtOAc and water/saturated NH₄Cl. Thelayers were separated and the aqueous phase extract with EtOAc (×2). Thecombined extracts were washed with brine, dried over Na₂SO₄, filtered,and concentrated. The resulting residue was purified by columnchromatography on a Biotage™ 50 g column eluted with 10% to 50% EtOAc:Hexanes to provide the desired product. LC-MS: calculated forC₂₆H₃₂ClIN₂O₅Si 642.08 observed m/e: 643.16 (M+H)⁺ (Rt 3.01/4 min).

Intermediate 2

(2R,3S,5R)-5-((6-chloro-5-iodo-1H-benzo[d]imidazol-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol

6-chloro-5-iodo-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole(1.3 g, 2.0 mmol) was dissolved in formic acid (10 ml, 261 mmol) andsaturated aqueous potassium hydrogen sulfate solution (1 ml, 1.454mmol). The reaction was heated to 40° C. for 3 h then, stirred overnightat rt. The reaction was cooled to 0° C. and diluted with EtOAc, then 3 MNaOH was added until a pH of pH 14 was reached and the reaction wasstirred 15 min. The solution was then neutralized to pH ˜8 withsaturated NH₄Cl. The layers were separated and the aqueous phase wasextracted with EtOAc (×2). The combined extracts were washed with brine,dried over Na₂SO₄, filtered, and concentrated. The resulting residue waspurified by column chromatography on a Biotage™ 50 g column eluted with1% to 30% MeOH in CHCl3 to provide the desired product. LC-MS:calculated for C₁₃H₁₄ClIN₂O₄ 423.97 observed m/e: 424.72 (M+H)⁺ (Rt1.06/2 min).

Intermediate 3

5-(4-bromophenyl)-6-chloro-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole

A reaction vessel was charged with(4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-ol (0.378 g,1.599 mmol),5-(4-bromophenyl)-6-chloro-2-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole(0.75 g, 1.454 mmol) and cesium carbonate (0.947 g, 2.91 mmol). Thesolids were dissolved in DMF (2.91 ml) and the reaction was stirred atrt for 18 h. The reaction was then diluted with EtOAc andwater/saturated NH₄Cl. The layers were separated and the aqueous phasewas extracted with EtOAc (×2). The combined extracts were washed withbrine, dried over Na₂SO₄, filtered, and concentrated. The resultingresidue was purified by column chromatography on a Biotage™ 50 g columneluted with 10% to 50% EtOAc: Hex to provide the desired product. LC-MS:calculated for C₃₂H₃₆BrClN₂O₅Si 672.12 observed m/e: 672.96 (M+H)⁺ (Rt1.43/2 min).

Intermediate 4

(2R,3S,5R)-5-((5-(4-bromophenyl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol

5-(4-bromophenyl)-6-chloro-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole(795 mg, 1.18 mmol) was dissolved in formic acid (10 ml, 261 mmol) andaq. sat. potassium hydrogen sulfate solution (1 ml, 1.454 mmol). Thereaction was heated to 40° C. for 6 h, and then stirred overnight at rt.The reaction mixture was cooled to 0° C. and diluted with EtOAc. 3 MNaOH was added until a pH of 14 was reached, the reaction was stirred 15min, and then neutralized to pH 8 with sat. NH₄Cl. The layers wereseparated and the aqueous phase extracted with EtOAc (×2). The combinedEtOAc extracts were washed with brine, dried over Na₂SO₄, filtered, andconcentrated. The resulting residue was purified by columnchromatography on a Biotage™ 50 g column eluted with 1% to 25% MeOH inCHCl3 to provide the desired product. LC-MS: calculated forC₁₉H₁₈BrClN₂O₄ 452.01 observed m/e: 452.81 (M+H)⁺ (Rt 1.15/2 min).

Intermediate 5

4,4,5,5-tetramethyl-2-(4′-((methylsulfonyl)methyl)-[1,1′-biphenyl]-4-yl)-1,3,2-dioxaborolane

1-bromo-4-((methylsulfonyl)methyl)benzene (1.5 g, 6.02 mmol),1,4-bis(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzene (4.97 g,15.05 mmol), and silver carbonate (1.826 g, 6.62 mmol) were dissolved inTHF (60.2 ml) and sparged with N₂ for 15 min. Pd(PPh₃)₄ (0.348 g, 0.301mmol) was added and the reaction was heated to 80° C. overnight. Thereaction was then cooled to rt, filtered through Celite™ andconcentrated in vacuo. The resulting residue was purified by columnchromatography on a Biotage™ 50 g column and eluted with 5% to 50%EtOAc:Hex to yield the desired compound. ¹H NMR δ (ppm) 7.83 (d, 2H),7.69 (d, 2H), 7.64 (d, 2H), 7.54 (d, 2H), 4.46 (s, 2H), 2.89 (s, 3H),1.4 (12H).

Intermediate 6

6-chloro-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-benzo[d]imidazole

To a stirred solution of6-chloro-5-iodo-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole(2.063 g, 3.21 mmol) under nitrogen in anhydrous THF (11.0 mL) was addedsilver carbonate (1.062 g, 3.85 mmol), Pd(PPh₃)₄ (185 mg, 0.160 mmol),and 1,4-benzenediboronic acid bis(pinacol) ester (3.18 g, 9.63 mmol).The mixture was cooled to −78° C., a hard vacuum was pulled, andnitrogen was introduced (3×). The mixture was allowed to warm to roomtemperature, then heated to reflux. After 24 hours, the mixture wascooled to room temperature and diluted with EtOAc (50 mL). The mixturewas filtered through Celite™ with ab EtOAc rinse until filtrate wascolorless. The filtrate was concentrated under reduced pressure. Theresultant residue was chromatographed using a Biotage™ 50 g (2×25 g inseries) silica gel cartridge eluted with 0-30% EtOAc in 1:1 Hex/DCM over25 column volumes. The product fractions were combined and concentratedunder reduced pressure, then the resultant oil was dissolved in MeCN andwater, frozen at −78° C., and lyophilized to dryness to provide thetitle compound as a yellow solid. LC-MS: calculated for C₃₈H₄₈BClN₂O₇Si718.30, observed m/e: 719.45 (M+H)⁺ (Rt 3.23/4 min).

Intermediate 7

4,6-difluoro-5-iodo-2-4(4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine

To a solution of4,6-difluoro-5-iodo-2-(methylsulfonyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine(3.4 g, 6.96 mmol) in 50 ml of DMF was added(4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-ol2 (2.47 g,10.44 mmol), and cesium carbonate (4.54 g, 13.93 mmol). The reaction wasstirred overnight at rt. The resulting solution was diluted with waterand EtOAc. The layers were separated and the aqueous phase was extractedwith EtOAc (×2). The combined extracts were washed with brine, driedover Na₂SO₄, filtered, and concentrated. Flash column chromatography onBiotage™ 340 g column eluted with 10% to 80% EtOAc in hexane yield thedesired product. LC-MS: m/e=644.83 (M+H)⁺ (Rt 1.39/2 min).

Intermediate 8

5-(4-bromophenyl)-4,6-difluoro-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine

A mixture of4,6-difluoro-5-iodo-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-1-((2-(trimethylsilylethoxy)methyl)-1H-benzo[d]imidazole(1.0 g, 1.552 mmol), (4-bromophenyl)-boronic acid (374 mg, 1.862 mmol),PdCl₂(dppf) (79 mg, 0.109 mmol), and lithium hydroxide (1.293 ml, 3.88mmol) were charged in a 10 ml reaction tube. The reaction was flushedwith N₂ for 5 min. Then de-gased dioxane (12 ml) was added, followed bywater (4 ml). The mixture was heated to 80 C overnight, then filteredthrough a funnel with an EtOAc rinse. The filtrate was concentrated, andthe resulting residue was purified on 40M column eluting with 10-40%EtOAc/hexane to the title compound. LC-MS: m/e: 675.17 (M+H)⁺ (Rt 3.25/4min).

Intermediate 9

4,6-difluoro-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)-methyl)-1H-benzo[d]imidazole

To a stirred solution of4,6-difluoro-5-iodo-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole(3.672 g, 5.70 mmol) under nitrogen in anhydrous THF (20.0 mL) was addedsilver carbonate (1.885 g, 6.84 mmol), Pd(PPh₃)₄ (329 mg, 0.285 mmol),and 1,4-benzenediboronic acid bis(pinacol) ester (5.64 g, 17.09 mmol).The mixture was cooled to −78° C., then a hard vacuum was pulled, andnitrogen was introduced (3×). The mixture was allowed to warm to roomtemperature, then heated to reflux. After 21 hours, the mixture wascooled to room temperature and diluted with EtOAc (50 mL). The mixturewas filtered through Celite™ with an EtOAc rinse until filtrate wascolorless. The filtrate was concentrated under reduced pressure. Theresultant residue was chromatographed using a Biotage™ 150 g (100 g+50 gin series) silica gel cartridge eluted with 0-20% EtOAc in 1:1 Hex/DCMover 25 column volumes. The product fractions were combined andconcentrated under reduced pressure to give an oil. The resultant oilwas dissolved in MeCN and water, frozen at −78° C., and lyophilized todryness to provide the title compound as a white solid. LC-MS:calculated for C₃₈H₄₇BF₂N₂O₇Si 720.32, observed m/e: 721.49 (M+H)⁺ (Rt3.20/4 min).

Example 1

(2R,3S,5R)-5-((6-chloro-5-(4-(pyrrolidin-1-yl)phenyl)-1H-benzo[d]imidazol-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol

1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidine(48.3 mg, 0.177 mmol) and(2R,3S,5R)-5-((6-chloro-5-iodo-1H-benzo[d]imidazol-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol(75 mg, 0.177 mmol) were dissolved in dioxane (600 μl) and water (600μl) and sparged with N₂ for 15 min. Then[1,1′-Bis(Diphenylphosphino)Ferrocene]Dichloropalladium (II) (25.8 mg,0.035 mmol) was added and the reaction was stirred 3 h at 80° C.,followed by dilution with water and EtOAc. The aqueous phase wasseparate, extracted with EtOAc (×2) and the combined extracts werewashed with brine, dried over Na₂SO₄, filtered and concentrated. Theresulting residue was purified by mass directed reverse phase HPLCeluted with acetonitrile in water containing 0.05% TFA. The desiredfractions were combined, diluted with EtOAc and washed with NaHCO₃. Theaqueous phase was extracted with EtOAc (×2) and the combined extractswere washed with brine, dried over Na₂SO₄, filtered and concentrated.The resulting residue was lyophilized from MeCN/water to give the titlecompound as a white solid. LC-MS: calculated for C₂₃H₂₆ClN₃O₄ 443.16observed m/e: 443.89 (M+H)⁺ (Rt 1.52/4 min); ¹H NMR δ (ppm) (CD₃OD):7.39 (s, 1H), 7.25-7.22 (m, 3H), 6.61 (d, 2H), 5.00 (septet, 1H),4.32-4.29 (m, 1H), 3.88 (dd, 1H), 3.66-3.58 (m, 2H), 3.36-3.30 (m, 5H),3.17-3.14 (m, 1H), 2.73-2.70 (m, 1H), 2.07-2.01 (m, 4H), 1.65 (q, 1H).

TABLE 1 Compounds prepared according to the methods in Example 1.Example HPLC-mass Number Structure spectum m/e 2

543.26 3

528.83

Example 4

(2R,3S,5R)-5-((6-chloro-5-(4′-(2-hydroxypropan-2-yl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol

2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ol(54.2 mg, 0.207 mmol) and(2R,3S,5R)-5-((5-(4-bromophenyl)-6-chloro-1H-benzo[d]imidazol-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol(75 mg, 0.165 mmol) were dissolved in dioxane (600 μl) and water (600μl) and the solution was sparged with N₂ for 15 min. Then[1,1′-Bis(Diphenylphosphino)Ferrocene]-Dichloropalladium(II) (24.19 mg,0.033 mmol) was added and the reaction was stirred for 3 h at 80° C.Then the reaction was diluted with water and EtOAc. The aqueous phasewas separated and extracted with EtOAc (×2), and the combined extractswere washed with brine, dried over Na₂SO₄, filtered and concentrated.The resulting residue was purified by mass directed reverse phase HPLCeluted with acetonitrile in water containing 0.1% formic acid. Thedesired fractions were combined and lyophilized to give the titlecompound as a white solid. LC-MS: calculated for C₂₈H₂₉ClN₂O₅ 508.18observed m/e: 508.90 (M+H)⁺ (Rt 1.14/2 min); ¹H NMR δ (ppm) (CD₃OD):7.67 (d, 2H), 7.64 (d, 2H), 7.58 (d, 2H), 7.48 (d, 2H), 7.46 (s, 1H),7.31 (s, 1H), 5.05-4.98 (m, 1H), 4.58-4.30 (m, 1H), 3.88 (dd, 1H),3.65-3.59 (m, 2H), 3.35 (t, 1H), 3.18-3.15 (m, 1H), 2.76-2.72 (m, 1H),1.66 (q, 1H), 1.58 (s, 6H).

Example 5

4′-(6-chloro-2-(((3R,5S,6R)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl)oxy)-1H-benzo[d]imidazol-5-yl)-2-fluoro-[1,1′-biphenyl]-4-carbonitrile

Placed 4-bromo-3-fluorobenzonitrile (13 mg, 0.065 mmol) andchloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium(II) (6mg, 0.012 mmol) into a reaction vessel in dry-glove box. Added6-chloro-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-benzo[d]imidazole(40 mg, 0.056 mmol) as a solution in anhydrous dioxane (0.50 mL) whichhad been degassed. To this mixture was added a solution of degassed,aqueous 1N K₃PO₄ (0.17 mL, 0.17 mmol). The reaction vessel was sealedand heated to 80° C. with stirring. After 16 hours, the mixture wasallowed to cool to room temperature. The mixture was diluted with DCM(2.0 mL) and water (1.0 mL) and vigorously stirred for 30 minutes. Theorganic layer was separated and concentrated under reduced pressure. Theresultant oil was dissolved in DCM (1.0 mL), SiliaMetS®Dimercaptotriazine (100 mg) was added, and the suspension was stirredfor 2 hours at 35° C. After cooling to room temperature, the mixture wasfiltered and concentrated under reduced pressure. The resultant residuewas dissolved in DCM (0.50 mL) and TFA (0.50 mL) and stirred at roomtemperature. After 3 hours the mixture was concentrated under reducedpressure. The resultant oil was dissolved in methanol (0.50 mL). A 5Naqueous solution of NaOH (0.10 mL) was added and the mixture was allowedto stir at room temperature. After 15 minutes the solution was acidifiedwith a few drops of formic acid and diluted with DMSO. Then the mixturewas filtered to remove solids and purified using reverse phasepreparatory HPLC using MeCN/water/formic acid as the mobile phase. Thefractions containing product were combined and concentrated underreduced pressure to provide the title compound as a white solid. LC-MS:calculated for C₂₆H₂₁ClFN₃O₄ 493.12, observed m/e: 494.12 (M+H)⁺ (Rt0.99/2 min)

TABLE 2 Compounds prepared according to the methods described in Example5. Example HPLC-mass Number Structure spectrum m/e  6

545.15  7

539.19  8

536.19  9

531.17 10

534.15 11

533.15 12

518.14 13

534.14 14

534.15 15

534.12 16

548.17 17

559.17 18

598.17 19

534.17 20

537.17 21

518.15 22

557.19 23

519.15 24

589.21

Example 25

(2R,3S,5R)-5-((5-([1,1′-biphenyl]-4-yl)-4,6-difluoro-1H-benzo[d]imidazol-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol

Step A: A mixture of(2R,3S,5R)-5-((4,6-difluoro-5-iodo-1H-imidazo[4,5-b]pyridin-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol(200 mg, 0.310 mmol), 4-biphenylboronic acid (73.7 mg, 0.372 mmol),PdCl₂(dppf) (31.8 mg, 0.043 mmol), and LiOH (310 ul, 3M, 0.931 mmol) indioxane (7 ml) was added to a reaction tube, which was sealed and N₂ forwas bubbled through for 5 min. The reaction was heated at 80 C for 2 h,then filtered with an EtOAc rinse. The filtrate was concentrated to givea residue, which was purified on 25M Biotage™ column eluting with 10-40%EtOAc/hexane to give the desired compound. LC-MS: m/e: 670.97 (M+H)⁺

Steps B and C: To a stirred solution of4,6-difluoro-5-iodo-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine(190 mg, 0.380 mmol) in formic acid (9 ml, 46.9 mmol) was addedpotassium hydrogen sulfate (1 ml, 0.549 mmol) at rt. The mixture wasstirred at 60 C for 2 h, then at rt overnight. Removed most of formicacid under reduced pressure and to the resulting residue was added 5 mlof THF and 3.0 M NaOH to pH 14. After stirring at rt for 60 min, thenthe reaction was neutralized with 2 N HCl to pH 7 and diluted with sat.NH₄Cl. The reaction was extracted with 3×25 ml EtOAc, dried over Na₂SO₄and evaporated under reduced pressure. The crude material was purifiedusing reverse phase HPLC injection eluting with 10-80% CH₃CN/H₂O withTFA as an additive to give the title product. LC-MS: m/e: 452.86 (M+H)⁺(Rt 3.24/4 min); ¹H NMR δ (ppm) (CD₃OD): 7.67 (d, 2H, J=8 Hz), 7.51-7.42(m, 2H), 7.36-7.28 (m, 1H), 5.01 (septet, 1H, J=6 Hz)), 4.34-4.29 (m,1H), 3.88 (dd, 1H, J=10, 4 Hz), 3.67-3.58 (m, 2H), 3.38-3.32 (m, 2H),3.19-3.14 (m, 1H), 2.76-2.70 (m, 1H), 1.64 (dd, 1H, J=23, 12 Hz).

TABLE 3 Compounds prepared according to the methods in Example 25.Example HPLC-mass Number Structure spectum m/e 26

530.88 27

544.97 28

446.03 29

510.96

Example 30

(2R,3S,5R)-5-((5-(4-(3,3-difluoropyrrolidin-1-yl)phenyl)-4,6-difluoro-1H-benzo[d]imidazol-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol

Step A:5-(4-bromophenyl)-4,6-difluoro-2-(((4aR,7R,8aS)-2phenylhexahydro-pyrano[3,2-d][1,3]dioxin-7-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine(100 mg, 0.148 mmol), 3,3-difluoropyrrolidine hydrochloride (32 mg,0.223 mol), Pd₂(dba)₃ (10.20 mg, 0.011 mmol),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (8.6 mg, 0.015 mmol),and cesium carbonate (290 mg, 0.891 mmol) were charged in a 10 mLreaction tube. The reaction tube was evacuated and backfilled with N₂(×3), then dioxane (2229 μl) was added and the reaction was heated to100° C. overnight. The reaction mixture was diluted with EtOAc andwater. The aqueous phase was separated and extracted with EtOAc (×2) andthe combined extracts were washed with brine, dried over Na₂SO₄,filtered, and concentrated. The resulting residue was purified by columnchromatography on a Biotage™ 10 g column eluted with 10% to 100%EtOAc:Hex. The desired fractions were collected and concentrated to givethe desired compound.

Steps B and C: To a stirred solution of(2R,3S,5R)-5-((5-(4-(3,3-difluoropyrrolidin-1-yl)phenyl)-4,6-difluoro-1H-benzo[d]imidazol-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol(59 mg, 0.080 mmol) in formic acid (3.6 ml, 94 mmol) was added potassiumhydrogen sulfate (0.4 ml, 0.081 mmol) at rt. The mixture was stirred at60 C for 3 h, then removed most of formic acid under reduced pressureand to the resulting residue was added 5 ml of THF and 3 M NaOH toadjust the reaction pH to pH 14. After stirring at rt for 60 min, thehydrolysis was complete and the reaction was neutralized with 2 N HCl topH 7. The reaction was diluted with sat. NH₄Cl, and extracted with 3×25ml EtOAc. The combined extracts were dried over Na₂SO₄ and evaporatedunder reduced pressure. The resulting crude material was purified onprep. TLC by eluting with 10% MeOH/1% NH₄OH/CH₂Cl₂ to afford the titlecompound. LC-MS: m/e: 482.15 (M+H)⁺ (Rt 1.95/4 min); ¹H NMR δ (ppm)(CD₃OD): 7.30 (d, 2H, J=8 Hz), 6.97 (d, 1H, J=8 Hz), 6.69 (d, 2H, J=8Hz), 5.02 (septet, 1H, J=6 Hz), 3.33-3.28 (m, 1H), 3.88 (dd, 1H, J=10, 2Hz), 3.70 (t, 1H, J=10 Hz), 3.67-3.52 (m, 4H), 3.37-3.33 (m, 2H),3.18-3.13 (m, 1H), 2.74-2.70 (m, 1H), 2.53 (septet, 2H, J=10 Hz), 1.64(dd, 1H, J=23, 12 Hz).

TABLE 4 Compounds prepared according to the methods in Example 30.Example HPLC-mass Number Structure spectum m/e 31

461.14 32

464.17 33

464.14

Example 34

(2R,3S,5R)-5-((4,6-difluoro-5-(4′-(5-methyl-1,2,4-oxadiazol-3-yl)-[1,1′-biphenyl]-4-yl)-1H-benzo[d]imidazol-2-yl)oxy)-2-(hydroxymethyl)tetrahydro-2H-pyran-3-ol

Placed 3-(4-bromophenyl)-5-methyl-1,2,4-oxadiazole (18 mg, 0.065 mmol)and chloro[(tri-tert-butylphosphine)-2-(2-aminobiphenyl)]palladium (II)(6 mg, 0.012 mmol) into a reaction vessel in a dry-glove box. Then4,6-difluoro-2-(((4aR,7R,8aS)-2-phenylhexahydro-pyrano[3,2-d][1,3]dioxin-7-yl)oxy)-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazole(45 mg, 0.062 mmol) was added as a solution in anhydrous dioxane (0.50mL) which had been degassed. To this mixture was added a solution ofdegassed, aqueous 1N K₃PO₄ (0.19 mL, 0.19 mmol). The reaction vessel wassealed and heated to 80° C. with stirring. After 16 hours, the mixturewas allowed to cool to room temperature. The mixture was then dilutedwith DCM (2.0 mL) and water (1.0 mL) and vigorously stirred for 30minutes. The organic layer was separated and concentrated under reducedpressure. The resultant oil was dissolved in DCM (1.0 mL), SiliaMetS®Dimercaptotriazine (100 mg) was added, and the suspension was stirredfor 2 hours at 35° C. After cooling to room temperature, the mixture wasfiltered and concentrated under reduced pressure. The resultant residuewas dissolved in DCM (0.50 mL) and TFA (0.50 mL) and stirred at roomtemperature. After 3 hours the mixture was concentrated under reducedpressure. The resultant oil was dissolved in methanol (0.50 mL). A 5Naqueous solution of NaOH (0.10 mL) was added and the mixture was allowedto stir at room temperature. After 15 minutes the solution was acidifiedwith a few drops of formic acid and diluted with DMSO. This mixture wasfiltered to remove solids and purified using reverse phase preparatoryHPLC using MeCN/water/formic acid as the mobile phase. The fractionscontaining product were combined and concentrated under reduced pressureto provide the title compound as a white solid. LC-MS: calculated forC₂₈H₂₄F₂N₄O₅ 534.17, observed m/e: 535.17 (M+H)⁺ (Rt 0.92/2 min).

TABLE 5 Compounds prepared according to the methods described in Example34. Example HPLC-mass Number Structure spectrum m/e 35

547.17 36

538.21 37

533.19 38

520.16 39

536.14 40

550.19 41

561.19 42

600.19 43

536.19 44

539.19 45

520.17 46

559.21 47

537.15 48

510.18 49

521.17 50

591.23

Biological Example 1 AMPKSAMSF (In Vitro AMPK Activation Assay)

The recombinant human AMPK complex 1 (containing α1β1γ1) or AMPK complex7 (containing α2β1γ1) was obtained from baculovirus expression system.Recombinant viruses were generated by cotransfection of AMPK/pBacPak9clones with Baculogold baculovirus DNA (Pharmingen) in spodopterafrugiperda 21 cells according to the manufacturer's instructions. Eachround of virus amplification was performed for 5 days in Grace's mediumcontaining 10% serum. Virus that had been subjected to three rounds ofamplification was used for all protein production procedures. To expressthe AMPK complex, sf21 cells were adapted to serum free medium (SF900II, Invitrogen) by sequential dilution from serum containing stocks intoSF900II medium and maintained in shaker flasks at 90 rpm at 27° C. Therecombinant AMPK enzyme complex was produced by triple infection, onerecombinant virus for each of the subunits, in sf21 cells under serumfree conditions. Cells were infected in log phase, 1×10⁶ cells/ml, at amultiplicity of infection of 5. Cells were harvested by centrifugationat 10,000×g for 15 minutes after 72 hours of infection with viruses. Theinsect cell pellet from 2 liters of culture was resuspended in 50 mllysis buffer (20 mM Tris-HCl, 50 mM NaCl, 50 mM NaF, 30 mM Na PPi, 0.25M sucrose, 10 mM ZnCl₂, 2 mM DTT, 0.4 mg/ml digitonin) and subjected totwo cycles of freeze-thaw lysis in a dry-ice ethanol bath. Insolublematerial was removed by centrifugation at 10,000×g and the supernatantwas fractionated with use of polyethylene glycol (PEG). The proteinfraction precipitating between 2.5 and 6% PEG was used for furtherpurification using a Blue-Sepharose step (Zhou et al, J. Clin. Invest.108, 1167-1174, 2001).

The in vitro AMPK activation assay is performed in a volume of 30 μl ina 384-well plate. Enzyme reactions were assembled in the microtiterplate by adding 15 μl of 2X enzyme in assay buffer (20 mM HEPES, pH 7.3,5 mM MgCl₂, 3 mM DTT, 0.01% Brij 35 and CamK Kinase, to activate AMPK)to wells which contained either DMSO or compound. The reaction wasinitiated with the addition of 15 μl 2× substrate mixture containing 200μM ATP, and 3.0 μM fluorescently labeled SAMS(5-FAM-HMRSAMSGLHLVKRR-COOH) in assay buffer. After 45-minute incubationat 25° C., the reaction was stopped by the addition of 70 μl stop buffer(100 mM HEPES, pH 7.3, 40 mM EDTA, 0.015% Brij 35). Phosphorylated 5-FAMSAMS product is assessed using a Caliper EZ Reader LabChip microfluidicsreader. Product conversion is determined by calculating the peak heightsof the substrate and product and reporting theproduct/(product+substrate) peak ratio. The 10-point titration data wereexpressed as % maximum AMP activation. The results were plotted using 4parameter fit and the inflection point reflecting 50% of the maximumactivation was reported as the EC₅₀. The % maximum AMP activation forselected compounds is provided in the table below.

The compounds of present invention, including the compounds of Examples1-50, were tested in the in vitro AMPK activation assay usingrecombinant human AMPK complex 1 (containing α1β1γ1) or AMPK complex 7(containing α2β1γ1), and were found to have greater than 50% maximum AMPactivation of human AMPK complex 1 (containing α1β1γ1) or AMPK complex 7(containing α2β1γ1), and EC₅₀ values of less than 50 micromolar.Preferred compounds of the present invention were found to have EC₅₀values of less than 0.1 micromolar in the in vitro AMPK activation assayusing recombinant human AMPK complex 1 or AMPK complex 7.

Maximum AMP Activation for Selected Compounds % Maximum % Maximum AMPEC₅₀ (nM) AMP EC₅₀ (nM) Activation of for human Activation of for humanExample human AMPK AMPK human AMPK AMPK No. Complex 1 Complex 1 Complex7 Complex 7 2 490 36 6 373 7 7 333 6 8 348 12 16 373 7 18 364 14 19 39215 21 400 9 23 387 18 24 360 18 26 558 7 29 492 26 35 370 3 36 327 3 38266 17 39 192 13 40 387 5 42 401 8 43 398 4 44 426 11 45 391 2 47 328 748 414 2 49 419 9 50 403 7

Biological Example 2 Phosphoroylation of Acetyl CoA Carboxylase by AMPKActivators in db/+Mice

To assess the potential for AMPK activators to increase thephosphorylation of Acetyl COA Carboxylase (ACC) in liver and skeletalmuscle, db/+ mice are dosed with AMPK activators at either 2 or 7 hprior to evaluation where phosphorylated ACC (p-ACC)/total ACC levelsare compared in the tissues of vehicle and compound treated mice.Briefly, mice are anesthetized using gas anesthesia with 1-4% isofluraneadministered to effect via nose cone. Once anesthetized, samples ofliver and skeletal muscle (gastrocnemius) are removed, snap frozen inliquid nitrogen, and homogenized. Homogenates are analyzed for proteinconcentration and equal amounts of protein are assayed for total andphosphorylated ACC (p-ACC) levels using Meso Scale Discovery'sMulti-array assay kit. MSD assay plates contain an electrode surfacethat is coated with streptavidin. Protein sample binds to streptavidin.The primary ACC or p-ACC specific antibody binds to protein and asecondary antibody labeled with MSD SULFO-TAG then binds to the primaryantibody. The electrode surface of the MSD plate responds to anelectrical stimulus and causes the SULFO-TAG labels bound to ACC andp-ACC to emit a light signal in proportion to the amount of p-ACC ortotal ACC present. The ratio of p-ACC/total ACC levels are determinedfor each sample and the ratio of p-ACC/total ACC levels for mice treatedwith AMPK activators is significantly elevated compared to the ratio ofthose treated with the vehicle control (significant elevations aredescribed as differences where p<0.05).

Biological Example 3 Inhibition of Fatty Acid Synthesis (FAS) by AMPKActivators in db/+Mice

To determine the effect of AMPK activators on Fatty Acid Synthesis (FAS)in the liver, the effect of oral pre-dosing of compounds on the amountof ³H incorporated into hepatic triglyceride is determined as describedby Sakurai T, Miyazawa S, Shindo Y, and T. Hashimoto (Biochim BiophysActa. 1974 Sep. 19; 360 (3):275-88). Briefly, mice (db/+, JacksonLaboratory, Maine) are orally dosed with AMPK activators at time=−8 h.Then at time=−1 h, mice are injected with 0.5 ml of 0.15 M NaClcontaining 0.2 mCi of ³H water per 100 g of body weight. At time 0, miceare sacrificed via cervical dislocation and livers are harvested for FASanalysis. To analyze livers for FAS, samples of liver are heated at 90°C. for 5 hours in a 4 M KOH/50% ethanol solution. Then the alkalinehydrolysate of liver is extracted with hexane and acidified to a pH<2with 10 M H2504. The fatty acids of liver are then extracted fromacidified hydrolysate with additional hexane, dried down with a streamof warm air, then re-suspended in scintillation fluid, and counted on abeta counter. The amount of fatty acids synthesized per gram of liver iscalculated based on the amount of ³H incorporated into hepatictriglyceride. The amount of ³H radiolabelled fatty acids synthesized inmice with treated with an AMPK activator is significantly less than theamount of ³H radiolabelled fatty acids synthesized in the control mice.

Biological Example 4 In Vivo Study for Therapy with an AMPK Activator inMice (Glucose Tolerance Test)

DIO mice are treated simultaneously with an effective dose of anAMPK-activated protein kinase activator.

Materials and Methods: Male C57BL/6NT mice (Taconic, 16-18 weeks old atthe beginning of the drug administration) are used. Mice are given waterand high fat diet D12492 (Research Diet Inc.) ad libitum. They are keptin an animal room which is maintained at 23±2 C temperature, 55±15%relative humidity and on a 12-hr light-dark cycle (7:00-19:00) during aquarantine and acclimatization period of 1 week. Animals are thenadministered vehicle (5 ml/kg of 0.5% methylcellulose in distilledwater) by oral gavage twice-daily at 9 AM and 5 PM. After 9 days, stablebody weight is observed. The following day (day −1), the mice are fastedfor 4 hours and tail bled to determine the glucose and insulin levels.Animals are sorted into groups based on plasma glucose, insulin levelsand body weight (n=8). The body weight and food in the hopper arerecorded on day 0 before compound dosing is initiated. One of the groupsis orally administered vehicle while the second group is administered anAMPK-activated protein kinase activator of the present invention at adose of 30 mg/kg (5 ml/kg) twice-daily for 12 days by gavage. Bodyweight and food intake are measured every other day. On day 5, theanimals are fasted 4 hours for measuring plasma glucose and insulinlevels after morning dosing. At day 12, body weight and food intake aremeasured and animals receive their last morning dose. Mice again arefasted 4 hours, blood is collected at a set time point (t=0 min), andthen challenged with dextrose orally (2 g/kg) Plasma glucose and insulinlevels are determined from tail bleeds taken at 20 and 90 minutes afterdextrose challenge. The plasma glucose and insulin excursion profilefrom t=0 to t=90 min is used to integrate an area under the curve (AUC)for each treatment. Percent inhibition values for each treatment aregenerated from the AUC data normalized to the C57BL/6NT mice feed withD7012. Preferred compounds of the present invention significantly reduceday 12 glucose and/or insulin AUC during the Oral Glucose Tolerance Testafter an oral dose in the range of 0.1 to 100 mg/kg.

Biological Example 5 Acute Food Intake Studies in Diet Induced Obese(DIO) Mice: General Procedure

Adult DIO mice are used in these studies. After at least 2 days ofacclimation to the vivarium conditions (controlled humidity andtemperature, lights on for 12 hours out of 24 hours) food (D12492(Research Diet Inc.) is removed from rodent cages. An AMPK activator ofthe present invention or the vehicle is administered orally,intraperitoneally, subcutaneously or intravenously before the return ofa known amount of food to cage. The optimal interval between dosing andfood presentation is based on the half-life of the compound based onwhen brain concentrations of the compound is the highest. Food remainingis measured at several intervals. Food intake is calculated as grams offood eaten per gram of body weight within each time interval and theappetite-suppressant effect of the AMPK activator is compared to theeffect of the vehicle. The food intake of mice treated with an AMPKactivator is significantly less than the food intake of control mice.

Biological Example 6 Chronic Weight Reduction Studies in Diet InducedObese (DIO) Mice: General Procedure

Adult DIO mice are used in these studies. Upon or soon after weaning,rats or mice are made obese due to exclusive access to diets containingfat and sucrose in higher proportions than in the control diet. The dietused to induce obesity is Research Diets D12451 chow (45% fat). Therodents ingest chow until they are significantly heavier and have ahigher proportion of body fat than control diet rats, often 9 weeks. Therodents receive injections (1 to 4 per day) or continuous infusions ofan AMPK activator of the present invention or the vehicle either orally,intraperitoneally, subcutaneously or intravenously. Food intake and bodyweights are measured daily or more frequently. Food intake is calculatedas grams of food eaten per gram of body weight within each time intervaland the appetite-suppressant and weight loss effect of the AMPKactivator of the present invention is compared to the effect of thevehicle. The weight loss of mice treated with an AMPK activator issignificantly greater than the weight loss of control mice.

Biological Example 7 Assay for Triglycerides

Adult DIO mice are used in these studies. Upon or soon after weaning,rats or mice are made obese due to exclusive access to diets containingfat and sucrose in higher proportions than in the control diet. The dietused to induce obesity is Research Diets D12451 chow (45% fat). Therodents ingest chow until they are significantly heavier and have ahigher proportion of body fat than control diet rats, often 9 weeks. Therodents receive injections (1 to 4 per day) or continuous infusions ofan AMPK activator of the present invention or the vehicle either orally,intraperitoneally, subcutaneously or intravenously. Food intake and bodyweights are measured daily or more frequently. Food intake is calculatedas grams of food eaten per gram of body weight within each time intervaland the appetite-suppressant and weight loss effect of the AMPKactivator of the present invention is compared to the effect of thevehicle. The weight loss of mice treated with an AMPK activator issignificantly greater than the weight loss of control mice.

Biological Example 8 Assay for Low HDL and/or High LDL

Adult DIO mice are used in these studies. Upon or soon after weaning,rats or mice are made obese due to exclusive access to diets containingfat and sucrose in higher proportions than in the control diet. The dietused to induce obesity is Research Diets D12451 chow (45% fat). Therodents ingest chow until they are significantly heavier and have ahigher proportion of body fat than control diet rats, often 9 weeks. Therodents receive injections (1 to 4 per day) or continuous infusions ofan AMPK activator of the present invention or the vehicle either orally,intraperitoneally, subcutaneously or intravenously. Food intake and bodyweights are measured daily or more frequently. Food intake is calculatedas grams of food eaten per gram of body weight within each time intervaland the appetite-suppressant and weight loss effect of the AMPKactivator of the present invention is compared to the effect of thevehicle. The weight loss of mice treated with an AMPK activator issignificantly greater than the weight loss of control mice.

Biological Example 9 Assay for Sarcopenia

Adult DIO mice are used in these studies. Upon or soon after weaning,rats or mice are made obese due to exclusive access to diets containingfat and sucrose in higher proportions than in the control diet. The dietused to induce obesity is Research Diets D12451 chow (45% fat). Therodents ingest chow until they are significantly heavier and have ahigher proportion of body fat than control diet rats, often 9 weeks. Therodents receive injections (1 to 4 per day) or continuous infusions ofan AMPK activator of the present invention or the vehicle either orally,intraperitoneally, subcutaneously or intravenously. Food intake and bodyweights are measured daily or more frequently. Food intake is calculatedas grams of food eaten per gram of body weight within each time intervaland the appetite-suppressant and weight loss effect of the AMPKactivator of the present invention is compared to the effect of thevehicle. The weight loss of mice treated with an AMPK activator issignificantly greater than the weight loss of control mice.

The scope of the claims should not be limited by the preferredembodiments set forth in the examples, but should be given the broadestinterpretation consistent with the description as a whole.

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the scope of the invention. Forexample, effective dosages other than the particular dosages as setforth herein above may be applicable as a consequence of variations inthe responsiveness of the mammal being treated for any of theindications for the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compound selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention.

What is claimed is:
 1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof, wherein: T is CR³; U isCR¹; V is CR²; W is CR⁴; X is —O—; Y is:

wherein Y is unsubstituted or substituted with 1, 2, 3, 4 or 5substituents selected from R^(b); Z is selected from: (1) NR⁵, (2) —S—,and (3) —O—; each R¹ is independently selected from: (1)aryl-C₂₋₁₀cycloheteroalkyl, and (2) aryl-aryl, wherein eachcycloheteroalkyl and aryl is unsubstituted or substituted with 1, 2, 3or 4 substituents independently selected from R^(a); R² is selected fromhalogen; R³ and R⁴ are each independently selected from: (1) hydrogen,(2) halogen, (3) —C₁₋₆alkyl, (4) —C₂₋₆alkenyl, (5) —C₂₋₆alkynyl, (6)—C₃₋₁₀cycloalkyl, (7) —C₃₋₁₀cycloalkenyl, (8) aryl, (9) heteroaryl, (10)—CN, (11) —CF₃, (12) —OH, (13) —OC₁₋₆alkyl, (14) —NH₂, (15)—NHC₁₋₆alkyl, (16) —N(C₁₋₆alkyl)₂, (17) —SC₁₋₆alkyl, (18) —SOC₁₋₆alkyl,(19) —SO₂C₁₋₆alkyl, (20) —NHSO₂C₁₋₆alkyl, (21) —NHC(O)C₁₋₆alkyl, (22)—SO₂NHC₁₋₆alkyl, and (23) —C(O)NHC₁₋₆alkyl; R⁵ is selected from: (1)hydrogen, (2) —C₁₋₆alkyl, (3) —C₂₋₆alkenyl, (4) —(CH₂)_(n)OH, (5)—CH₂CO₂H, and (6) —CH₂CO₂C₁₋₆alkyl; each R^(a) is independently selectedfrom the group consisting of: (1) —(CH₂)_(m)-halogen, (2) oxo, (3)—(CH₂)_(m)OH, (4) —(CH₂)_(m)N(R^(j))₂, (5) —(CH₂)_(m)NO₂, (6)—(CH₂)_(m)CN, (7) —C₁₋₆alkyl, (8) —(CH₂)_(m)CF₃, (9) —(CH₂)_(m)OCF₃,(10) —O—(CH₂)_(m)—OC₁₋₆ alkyl, (11) —(CH₂)_(m)N(R^(j))C(O)R^(f), (12)—(CH₂)_(m)N(R^(j))CO₂R^(f), (13) —(CH₂)_(m)C(═N—OH)N(R^(j))₂, (14)—(CH₂)_(m)OC₁₋₆alkyl, (15) —(CH₂)_(m)O—(CH₂)_(m)—C₃₋₇cycloalkyl, (16)—(CH₂)_(m)O—(CH₂)_(m)—C₂₋₇cycloheteroalkyl, (17)—(CH₂)_(m)O—(CH₂)_(m)-aryl, (18) —(CH₂)_(m)O—(CH₂)_(m)-heteroaryl, (19)—(CH₂)_(m)SC₁₋₆alkyl, (20) —(CH₂)_(m)S(O)C₁₋₆alkyl, (21)—(CH₂)_(m)SO₂C₁₋₆alkyl, (22) —(CH₂)_(m)SO₂(CH₂)_(m)—C₃₋₇cycloalkyl, (23)—(CH₂)_(m)SO₂(CH₂)_(m)—C₂₋₇cycloheteroalkyl, (24)—(CH₂)_(m)SO₂(CH₂)_(m)-aryl, (25) —(CH₂)_(m)SO₂(CH₂)_(m)-heteroaryl,(26) —(CH₂)_(m)SO₂NH₂, (27) —(CH₂)_(m)SO₂NHC₁₋₆alkyl, (28)—(CH₂)_(m)SO₂NHC₃₋₇cycloalkyl, (29) —(CH₂)_(m)SO₂NHC₂₋₇cycloheteroalkyl,(30) —(CH₂)_(m)SO₂NH-aryl, (31) —(CH₂)_(m)SO₂NH-heteroaryl, (32)—(CH₂)_(m)NHSO₂C₁₋₆alkyl, (33) —(CH₂)_(m)NHSO₂—C₃₋₇cycloalkyl, (34)—(CH₂)_(m)NHSO₂—C₂₋₇cycloheteroalkyl, (35) —(CH₂)_(m)NHSO₂-aryl, (36)—(CH₂)_(m)NHSO₂NH-heteroaryl, (37) —(CH₂)_(m)N(R^(j))—C₁₋₆alkyl, (38)—(CH₂)_(m)N(R^(j))—C₃₋₇cycloalkyl, (39)—(CH₂)_(m)N(R^(j))—C₂₋₇cycloheteroalkyl, (40)—(CH₂)_(m)N(R^(j))—C₂₋₇cycloheteroalkenyl, (41) —(CH₂)_(m)N(R^(j))-aryl,(42) —(CH₂)_(m)N(R^(i))-heteroaryl, (43) —(CH₂)_(m)C(O)R^(f), (44)—(CH₂)_(m)C(O)N(R^(j))₂, (45) —(CH₂)_(m)N(R^(j))C(O)N(R^(j))₂, (46)—(CH₂)_(m)CO₂H, (47) —(CH₂)_(m)OCOH, (48) —(CH₂)_(m)CO₂R^(f), (49)—(CH₂)_(m)OCOR^(f), (50) —(CH₂)_(m)C₃₋₇cycloalkyl, (51)—(CH₂)_(m)C₃₋₇cycloalkenyl, (52) —(CH₂)_(m)C₂₋₆cycloheteroalkyl, (53)—(CH₂)_(m)C₂₋₆cycloheteroalkenyl, (54) —(CH₂)_(m)aryl, and (55)—(CH₂)_(m)heteroaryl, wherein each CH₂ is unsubstituted or substitutedwith 1 or 2 substituents selected from: —OH, —(CH₂)₁₋₃OH, —CN, —NH₂,—NH(C₁₋₆alkyl)₂, oxo, —C₁₋₆alkyl, —C₁₋₆ alkyl substituted with 1-5 OH,—OC₁₋₆alkyl, halogen, —CH₂F, —CF₃, —CO₂H, —CO₂C₁₋₆alkyl,—C₃₋₇cycloalkyl, phenyl, CH₂phenyl, heteroaryl and CH₂heteroaryl, andwherein alkyl, cycloalkyl, cycloalkenyl, cycloheteroalkyl,cycloheteroalkenyl, aryl and heteroaryl are unsubstituted or substitutedwith 1, 2, 3 or 4 substituents selected from: oxo, —OH, —(CH₂)₁₋₅OH,—(CH₂)₁₋₅CN, —CN, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆alkyl,—C₁₋₆alkyl substituted with 1-5 OH, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂,—CF₃, —(CH₂)₁₋₅CF₃ optionally substituted with 1, 2 or 3 —OH, —CO₂H,—CO₂C₁₋₆alkyl, —SO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl, phenyl, CH₂phenyl,heteroaryl and CH₂heteroaryl; each R^(b) is independently selected from:(1) hydrogen, (2) —C₁₋₆alkyl, (3) —C₂₋₆alkenyl, (4)—(CH₂)_(n)—C₃₋₁₀cycloalkyl, (5) —(CH₂)_(n)—C₃₋₁₀cycloalkenyl, (6)—(CH₂)_(n)—C₂₋₁₀cycloheteroalkyl, (7)—(CH₂)_(n)—C₂₋₁₀cycloheteroalkenyl, (8) —(CH₂)_(n)-aryl, (9)—(CH₂)_(n)-heteroaryl, (10) oxo, (11) —(CH₂)_(n)—CF₃, (12)—(CH₂)_(n)—CN, (13) —(CH₂)_(t)-halogen, (14) —(CH₂)_(s)—OH, (15)—(CH₂)_(n)—NO₂, (16) —(CH₂)_(n)—NH₂, (17) —(CH₂)_(n)—NH(C₁₋₆alkyl), (18)—(CH₂)_(n)—N(C₁₋₆alkyl)₂, (19) —(CH₂)_(n)—NHCO₂H, (20) —(CH₂)_(n)—OC₁₋₆alkyl, (21) —(CH₂)_(n)—OC₂₋₆alkenyl, (22) —(CH₂)_(n)—COC₁₋₆alkyl, (23)—(CH₂)_(n)—CO₂H, (24) —(CH₂)_(n)—OCOH, (25) —(CH₂)_(n)—CO₂R^(i), (26)—(CH₂)_(n)—OC(O)R^(i), (27) —(CH₂)_(q)—C(O)N(R^(e))₂, (28)—(CH₂)_(q)—CO₂N(R^(e))₂, (29) —(CH₂)_(n)—C(O)(CH₂)_(n)N(R^(g))₂, (30)—(CH₂)_(n)—OC(O)(CH₂)_(n)N(R^(g))₂, (31)—(CH₂)_(n)—N(R^(e))C(O)C₁₋₆alkyl, (32) —(CH₂)_(n)—N(R^(e))SO₂R^(i), (33)—(CH₂)_(n)—SO₂C₁₋₆alkyl, (34) —(CH₂)_(n)—SO₂N(R^(e))R^(g), (35)—(CH₂)_(n)—SO₂N(R^(e))C(O)R^(i), (36) —(CH₂)_(n)—SO₂N(R^(e))CO₂R^(i),(37) —(CH₂)_(n)—SO₂N(R^(e))CON(R^(g))₂, (38)—(CH₂)_(n)—C(O)N(R^(e))SO₂R^(i), (39) —(CH₂)_(n)—N(R^(e))C(O)N(R^(g))₂,(40) ═N(OH), and (41) ═N(OC₁₋₆alkyl), wherein each CH₂ is unsubstitutedor substituted with 1 or 2 substituents selected from: —C₁₋₆alkyl, —OH,halogen and —NH₂ wherein each NH is unsubstituted or substituted with 1substituent selected from R^(c), and wherein each alkyl, cycloalkyl,cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl and heteroarylis unsubstituted or substituted with 1, 2, 3 or 4 substituents selectedfrom R^(c), or wherein two R^(b) substituents and the carbon to whichthey are attached may form a 3 to 6 membered cycloalkyl ring, a 3-6membered cycloalkenyl ring, a 3-6 membered cycloheteroalkyl ring or a3-6 membered cycloheteroalkenyl ring, wherein the ring is unsubstitutedor substituted with 1, 2, 3 or 4 substituents selected from R^(c); eachR^(c) is independently selected from: (1) halogen, (2) oxo, (3)—(CH₂)_(r)OH, (4) —(CH₂)_(r)N(R^(e))₂, (5) —(CH₂)_(r)CN, (6) —C₁₋₆alkyl,(7) —CF₃, (8) —C₁₋₆alkyl-OH, (9) —OCH₂OC₁₋₆alkyl, (10)—(CH₂)_(r)OC₁₋₆alkyl, (11) —OCH₂aryl, (12) —(CH₂)_(r)SC₁₋₆alkyl, (13)—(CH₂)_(r)C(O)R^(f), (14) —(CH₂)_(r)C(O)N(R^(e))₂, (15) —(CH₂)_(r)CO₂H,(16) —(CH₂)_(r)CO₂R^(f), (17) —(CH₂)_(r)C₃₋₇cycloalkyl, (18)—(CH₂)_(r)C₂₋₆cycloheteroalkyl, (19) —(CH₂)_(r)aryl, and (20)—(CH₂)_(r)heteroaryl, wherein each CH₂ is unsubstituted or substitutedwith 1 or 2 substituents selected from: oxo, —OH, —CN, —N(R^(h))₂,—C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, —CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl and heteroaryl, and wherein alkyl, cycloalkyl,cycloheteroalkyl, aryl and heteroaryl are unsubstituted or substitutedwith 1, 2, 3 or 4 substituents selected from: oxo, —OH, —CN, —N(R^(h))₂,—C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃, —CO₂H, —CO₂C₁₋₆alkyl, —C₃₋₇cycloalkyl and heteroaryl; each R^(e), R^(g) and R^(h) isindependently selected from: (1) hydrogen, (2) —C₁₋₆alkyl, and (3)—O—C₁₋₆alkyl, wherein alkyl is unsubstituted or substituted with 1, 2, 3or 4 substituents selected from: —OH, oxo, halogen, C₁₋₆alkyl,—OC₁₋₆alkyl, —NH₂, —NH(C₁₋₆alkyl), and —N(C₁₋₆alkyl)₂; each R^(j) isindependently selected from: (1) hydrogen, (2) C₁₋₆alkyl, (3)C₃₋₆cycloalkyl, (4) —C(O)R^(i), (5) —CO₂R^(i), and (6) —SO₂R^(i),wherein alkyl and cycloalkyl are unsubstituted or substituted with 1, 2,3 or 4 substituents selected from: —OH, oxo, halogen, C₁₋₆alkyl,—OC₁₋₆alkyl, —NH₂, —NH(C₁₋₆alkyl), and —N(C₁₋₆ alkyl)₂; each R^(f) andR^(i) is independently selected from: (1) C₁₋₆alkyl, (2)—(CH₂)_(r)C₄₋₇cycloalkyl, (3) —(CH₂)_(r)C₄₋₇cycloalkenyl, (4)—(CH₂)_(r)C₃₋₇cycloheteroalkyl, (5) —(CH₂)_(r)C₃₋₇cycloheteroalkenyl,(6) —(CH₂)_(r)aryl, and (7) —(CH₂)_(r)heteroaryl, wherein alkyl,cycloalkyl, cycloalkenyl, cycloheteroalkyl, cycloheteroalkenyl, aryl andheteroaryl are unsubstituted or substituted with 1, 2, 3 or 4substituents selected from: oxo, —OH, —CN, —NH₂, —NH(C₁₋₆alkyl),—N(C₁₋₆alkyl)₂, —C₁₋₆alkyl, —OC₁₋₆alkyl, halogen, —CH₂F, —CHF₂, —CF₃,—CO₂H, —CO₂C₁₋₆ alkyl, —C₃₋₇cycloalkyl, and heteroaryl; n is 0, 1, 2, 3or 4; m is 0, 1, 2, 3 or 4; q is 0, 1, 2, 3 or 4; r is 0, 1 or 2; s is0, 1, 2, 3 or 4; t is 0, 1, 2, 3 or 4, and u is 0, 1, 2, 3 or
 4. 2. Thecompound according to claim 1 wherein T is CR³; U is CR¹; V is CR²; andW is CR⁴, wherein R³ is hydrogen or halogen; or a pharmaceuticallyacceptable salt thereof.
 3. The compound according to claim 1 wherein Tis CR³; U is CR¹; V is CR²; and W is CR⁴, wherein R³ is hydrogen orhalogen; and R² is halogen; or a pharmaceutically acceptable saltthereof.
 4. The compound according to claim 1, wherein T is CR³; U isCR¹; V is CR²; and W is CR⁴, wherein R³ is hydrogen or halogen; R² ishalogen; and R⁴ is hydrogen; or a pharmaceutically acceptable saltthereof.
 5. The compound according to claim 1, wherein Y is:

wherein Y is unsubstituted or substituted with 1, 2, 3, 4 or 5substituents selected from R^(b); or a pharmaceutically acceptable saltthereof.
 6. The compound according to claim 1, wherein Y is:

wherein Y is unsubstituted or substituted with 1, 2 or 3 substituentsselected from R^(b); or a pharmaceutically acceptable salt thereof. 7.The compound according to claim 1, wherein Z is NR⁵; or apharmaceutically acceptable salt thereof.
 8. The compound according toclaim 1, wherein each R¹ is independently selected from: (1)phenyl-pyrrolidine, and (2) biphenyl, wherein each pyrrolidine andphenyl is unsubstituted or substituted with 1, 2, 3 or 4 substituentsindependently selected from R^(a), and R² is selected from halogen; or apharmaceutically acceptable salt thereof.
 9. The compound according toclaim 1, wherein each R¹ is independently selected from: aryl-aryl,wherein each aryl is unsubstituted or substituted with 1, 2, 3 or 4substituents independently selected from R^(a), and R² is halogen; or apharmaceutically acceptable salt thereof.
 10. The compound according toclaim 1, wherein R³ is hydrogen or halogen; R⁴ is hydrogen; and R⁵ ishydrogen; or a pharmaceutically acceptable salt thereof.
 11. Thecompound according to claim 1, wherein R³ is hydrogen or F; R⁴ ishydrogen; and R⁵ is hydrogen; or a pharmaceutically acceptable saltthereof.
 12. The compound according to claim 1 wherein: T is CR³; U isCR¹; V is CR²; W is CR⁴; X is —O—; Y is:

wherein Y is unsubstituted or substituted with 1, 2, 3, 4 or 5substituents selected from R^(b); Z is NR⁵; each R¹ is independentlyselected from: (1) aryl-C₂₋₁₀cycloheteroalkyl, and (2) aryl-aryl,wherein each cycloheteroalkyl and aryl is unsubstituted or substitutedwith 1, 2, 3 or 4 substituents independently selected from R^(a); R² ishalogen; R³ is hydrogen or halogen; R⁴ is hydrogen; and R⁵ is hydrogen;or a pharmaceutically acceptable salt thereof.
 13. The compoundaccording to claim 1 wherein: T is CR³; U is CR¹; V is CR²; W is CR⁴; Xis —O—; Y is:

wherein Y is unsubstituted or substituted with 1, 2 or 3 substituentsselected from R^(b); Z is NR⁵; each R¹ is independently selected from:aryl-aryl, wherein each aryl is unsubstituted or substituted with 1, 2,3 or 4 substituents independently selected from R^(a); R² is halogen; R³is hydrogen or halogen; R⁴ is hydrogen; and R⁵ is hydrogen; or apharmaceutically acceptable salt thereof.
 14. The compound according toclaim 1, selected from:

or a pharmaceutically acceptable salt thereof.
 15. A compositioncomprising a compound of claim 1, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier.
 16. A compositioncomprising a compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, and a compound selected from simvastatin,ezetimibe and sitagliptin; and a pharmaceutically acceptable carrier.17. A method of treating type 2 diabetes mellitus in a patient in needof treatment comprising the administration to the patient of atherapeutically effective amount of a compound of claim 1, or apharmaceutically acceptable salt thereof.